Opioid salts and formulations exhibiting anti-abuse and anti-dumping properties

ABSTRACT

A drug substance with a pharmaceutically acceptable organic acid addition salt of an opioid wherein said organic acid is selected from Structure A: 
     
       
         
         
             
             
         
       
         
         wherein R 1 -R 4  are independently selected from H, alkyl or substituted alkyl of 1-6 carbons, adjacent groups may be taken together to form a cyclic alkyl, cyclic alkyl-aryl, or cyclic aryl moiety; 
         R 5  is selected from H, or an alkali earth cation; 
         R 6  and R 7  are independently selected from H, alkyl of 1-6 carbons, an alkali earth cation, and aryl of 6 to 12 carbons, in a number sufficient to complete the valence bonding of X, and 
         wherein X is selected from nitrogen, oxygen or sulfur; and 
         wherein the drug substance has a morphology selected from amorphous and crystalline.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is divisional application of pending U.S. patentapplication Ser. No. 13/211,718 filed Aug. 17, 2011 which is adivisional application of pending U.S. patent application Ser. No.12/423,641 filed Jun. 17, 2009 which is a continuation-in-partapplication of pending U.S. patent application Ser. Nos. 11/805,225filed May 22, 2007; 11/973,252 filed Oct. 5, 2007; 12/080,514 filed Apr.3, 2008; 12/080,513 filed Apr. 3, 2008 and 12/080,531 filed Apr. 3, 2008all of which are incorporated herein by reference. The presentapplication is related to U.S. patent application Ser. Nos. 11/595,379filed Nov. 10, 2006 now U.S. Pat. No. 7,718,649; 11/843,690 filed Aug.23, 2007 now U.S. Pat. No. 8,039,461; 11/928,592 filed Oct. 30, 2007 and11/932,336 filed Oct. 31, 2007 now U.S. Pat. No. 7,858,663 each of whichis incorporated herein by reference.

BACKGROUND OF THE INVENTION

The abuse of controlled substances in the United States and other partsof the world has reached epidemic proportions. To address this humantragedy significant administrative and technical resources are currentlybeing expended to identify and implement technologies which deter,inhibit or prevent the unintentional, illicit, illegal and/orrecreational use of controlled substances. Within the context of thisdiscussion controlled substances are those identified by the US DrugEnforcement Administration (DEA) and as context of discussion herein maydictate, the controlled substance may either be the activepharmaceutical ingredient (as its free base or salt) or the formulateddrug product. Further, the controlled substances of interest to thisinvention are the opioid narcotics—that is, the alkaloids derived fromopium either by isolation from natural sources, semi-syntheticderivatives prepared by transformation of the natural isolates,synthetic acquisition and combinations thereof. A useful overview is“Opium and Its Alkaloids” found in the American Journal ofPharmaceutical Education, Vol. 66, Summer 2002, pp. 186-194.

The detrimental practice of drug abuse, particularly of oxycodone, theactive ingredient in OxyContin®, is well recognized. Indeed, in December2003 the General Accounting Office (GAO) issued a report toCongressional requesters entitled “Prescription Drugs, OxyContin Abuseand Diversion and Efforts to Address the Problem”. The document containsa statistical assessment indicating the severity of the abuse problem,the employment of marketing practices contrary to FDA regulations, theactions taken by Purdue Pharma, Federal and State Agencies tasked toprevent abuse and diversion of Oxycontin® while recognizing thelegitimate medical necessity of the opioid narcotics to treat pain. Likemany governmental reports, the GAO's assessment was thorough andpresented a factual basis to the problem of Oxycontin® abuse. However,the report contained a “Recommendation for Executive Action” whichessentially returned the problem to the FDA as indicated by thefollowing excerpted paragraph.

“To improve the efforts to prevent or identify the abuse and diversionof schedule II controlled substances, we recommend that the Commissionerof Food and Drugs ensure that FDA's risk management plan guidanceencourages pharmaceutical manufactures that submit new drug applicationfor these substances to include plans that contain a strategy formonitoring the use of these drugs and identifying potential abuses anddiversion problems.”

Indeed, the FDA has several “Guidance for Industry” documents,namely: 1) Development and Use of Risk Minimization Action Plans, 2)Pre-marketing Risk Assessment, and e) Good Pharmacovigilance Practicesand Pharmacoepidemiologic Assessment. In the first cited Guidance thefollowing excerpt is particularly poignant to this discussion:

“Opiate drug products have important benefits in alleviating pain butare associated with significant risk of overdose, abuse, and addiction.The Agency recommends that sponsors of Schedule II controlledsubstances, including Schedule II extended release or high concentrationopiate drug products, consider developing RiskMAPS for these products.”[Note: RiskMAPS=risk minimization action plans.]

These Guidances, while well intended, employ administrative measures inan attempt to prevent drug abuse. As an example, the FDA recommends theRiskMAP to be designed according to the following criteria: 1)compatible with current technology, 2) applicable to both outpatient andinpatient use, 3) accessible to patients in diverse locales, includingnon-urban settings, and 4) consistent with existing tools and programs,or systems that have been shown to be effective with similar products,indications, or risks.

Again, the abuse of controlled substances in the United States hasreached epidemic proportions which has yielded a significant economicburden on society and has seriously impacted the general healthcondition of the nation's society. While the origin of the abuse may beaccredited to the irresponsible behavior of the abuser, the detrimentaleffects to society remain. For more than twenty-five years, the actionsby the federal and state governments have had no apparent impact on thedrug abuse crisis and the problem has escalated faster than thepopulation's growth rate. Similarly, educational programs andintervention by the medical community have had limited effect. Indeed,those individuals who on their own initiative or through the assistanceof family or friends who have sought help through drug addictiontreatment programs have also responded poorly. In fact, the behavioraland/or physiological change needed to eliminate their abuse/dependenceon controlled substances is usually only temporary. This is especiallyevident when you consider the rising epidemic in methadone abuse withthe frequent occurrence of such abuse leading to death of the “patient”;i.e. even the treatment is leading to death.

In the context of public health, controlled substances fulfill medicalnecessities and will be required to treat legitimate ailments in bothcontrolled environments (clinics, hospitals, alternate care sites) aswell as in unmonitored circumstances (drug administration by thepatient). Medical professionals, alert to the potential for drug abuseand diversion, attempt to restrict the use of various drugs particularlypain relief medications such as Oxycontin®. Unfortunately, this approachis inconsistent and may deny relief to patients truly suffering frompain. To the medical practitioner, the decision to prescribe, or not toprescribe, pain medication is agonizing and may be accompanied by legalliability. In regard to non-prescription drug products, the “decision”to restrict availability of pseudoephedrine containing products byrequiring the pharmacy to stock and track these products from“behind-the-counter” also impedes the legitimate use of these productsand places an undue burden on the pharmacist and the consumer. Ofcourse, this action was taken in an effort to stem the trade of theseproducts for their use in illicit methamphetamine production.

An additional burden is placed on the medical practitioner as drug abusecontinues to escalate and is not limited to the abuse of “traditional”illegal/recreational drugs of previous generations but abuse practiceshave now broadened to include legitimate prescription drugs. A full-pageadvertisement was sponsored by eleven professional medical organizationsin the Feb. 10, 2008 edition of The New York Times page A7 indicatingthat “teens abuse prescription drugs more than any illicit street drugexcept marijuana”. The advertisement further extols “prescription drugsare the drugs of choice for 12 and 13 year olds” and that “every day,2500 kids age 12 to 17 try a painkiller for the first time”. Simplystated, teens are raiding the family medicine cabinet to get high. Infact, The Wall Street Journal Online of Mar. 25, 2008 reported in anarticle by Elizabeth Bernstein entitled “New Addiction on Campus:Raiding the Medicine Cabinet”, the increased prevalence of 18-25 yearsolds abusing prescription narcotics primarily due to their readyavailability. In January 2008, the Office of National Drug ControlPolicy, under the authority of the Executive Office of the President,published “Prescription for Danger, A Report on the Troubling Trend ofPrescription and Over-the-Counter Drug Abuse Among the Nation's Teens”.This report summarizes the crisis well and adds additional insight tothe problem. For instance, “teens are abusing prescription drugs becausemany believe the myth that these drugs provide a “safe” high and theyare easily available”. Statistically, it would appear parenting skillsare ineffective and may only have limited influence on preventing a teenfrom abusing drugs.

Government initiatives to curb drug abuse, the heightened awarenessamong medical professionals for observing symptoms of drug abuse or forrecognizing the potential for such abuse, and parental guidance have allapparently remained ineffective.

Within the last few years, the pharmaceutical industry has responded tothis difficult problem in an attempt to provide controlled substancedrug products possessing anti-abuse features. There are essentiallythree “classical” technical approaches to imparting abuse resistantproperties to controlled substances: 1) through a prodrug, 2) via anintractable matrix formulation technique, and 3) by antagonistincorporation into the product formulation. Each approach has been shownto have significant limitations for universal application to a broadrange of products. The intent is to impart anti-abuse properties to adrug product via formulation mechanisms which modulate the physicaland/or chemical properties of the drug dosage product. This approach mayemploy admixtures of various excipients, drug antagonists, or utilizeproduction techniques, and combinations thereof to achieve some level ofanti-abuse product feature. To date this approach has been relativelyineffective. For instance, Purdue Pharma recently (May 2008) was subjectto a regulatory submission review by a panel of FDA experts regardingNew Drug Application 22-272 Reformulated Oxycontin®. Panelists'expressed displeasure about the lack of abuse-prevention data and the“poor scientific rigor” as reported in the Wall Street Journal. Purdue'sintention was to prepare a tamper-resistant form of the productemploying a polymeric excipient which prevented manipulation to anabusable, injectable form.

In contrast to these formulation techniques, anti-abuse properties maybe addressed through the drug substance, also known as the activepharmaceutical ingredient (API). At the API level, the physical and/orchemical properties necessary to impart anti-abuse features to theformulated drug product are introduced while maintaining the desiredtherapeutic value of the drug substance. Two broad categories to thisapproach have been utilized: 1) the preparation of prodrugs, and 2) theselection of novel salts of the API which exhibit anti-abuse features.

In regard to the prodrug approach, the most celebrated example is theFDA approved product Vyvanse™. Vyvanse™ is a formulated product forsolid oral dose administration and employs a prodrug of amphetamine. TheFDA's Orange Book refers to two patents covering this technology; U.S.Pat. No. 7,105,486 and U.S. Pat. No. 7,223,735. The anti-abuse featureof Vyvanse™ arises from the drug substance being released only afteringestion and subsequent hydrolysis by enzymes located in the epithelialcells of the intestine. Attempts to abuse the drug by other means areprevented because of the absence of the enzyme.

In co-pending U.S. patent application Ser. No. 11/805,225[Bristol, etal.] entitled “Salts of Physiologically Active and PsychoactiveAlkaloids and Amines Simultaneously Exhibiting Bioavailability and AbuseResistance”, incorporated herein in its entirety, a number of“classical” formulation and prodrug approaches are referenced whichallegedly impart anti-abuse properties to drug substances and to drugproducts. However, Bristol teaches how the careful selection of organicacid addition salts of amine-containing controlled substances can beprepared which exhibit anti-abuse properties; one factor of several forthis desired feature results from the salt's lack of solubility in themucosal membranes of humans (or animals). In contrast, the salts whensubjected to the gastro-intestinal tract were transformed andbio-available. The co-pending application describes a platform approachto introducing anti-abuse properties to controlled substances.

Further, in co-pending U.S. patent application Ser. No. 11/928,592[King, et al.] entitled “Drug Release Properties of PolymorphicPharmaceutical Substances”, incorporated herein in its entirety, thedissolution profiles associated with various organic acid salts ofamine-containing controlled substances is disclosed. In conjunction withthe salts lacking solubility in the mucosal membranes, the in vitrodissolution testing of these salts indicated polymorphic behaviorssuitable for controlled and targeted release. Consequently, theselection of an organic acid addition salt and of a particular polymorphassociated with that salt, provide a means to impart substantialanti-abuse properties into controlled substance drug products.

Drug abuse, in particular controlled substance abuse, is a difficultproblem to curtail. There are behavioral aspects to the abuse which maynot surrender to any reasonably available solution. For instance, anindividual's choice to deliberately swallow multiple doses of alegitimately prescribed oral dosage is nearly impossible to control. Thecontrolled release product approach has had limited effect in mitigatingthis occurrence. Alternatively, there are proposed product formulationswhich contain low amounts of an emetic such that when used in theintended dosing regimen the individual is unaffected by the emetic.However, with an intentional oral overdose, the cumulative amounts ofemetic from multiple doses results in emesis (and supposedly theextirpation by vomiting of the controlled substance). Consequently, drugabuse while retaining the definition employed above, may also beconsidered that activity wherein the controlled substance is employed ina route of administration other than by which the product was designedor intended.

It is clear that administrative efforts and chemical technologies willbe needed and employed in combination to impede the practice of drugabuse. In co-pending U.S. patent application Ser. No. 11/973,252 filedon Oct. 5, 2007[King et al.], incorporated herein by reference in itsentirety, a process is disclosed which employs anti-abuse properties ofselected organic acid salts of amine-containing controlled substancesand which provides track and trace capabilities through computerdatabases. The invention provides enablement to the FDA's initiative todevelop a new guidance for a similar to, but the chemically comparabletopic of, anti-counterfeiting. The FDA's proposed guidance, entitled“Incorporation of Physical-Chemical Identifiers (PCID) into Solid OralDosage Form Drug Products for Anti-counterfeiting” is also applicable tothe cradle-to-grave administrative monitoring of controlled substances.Indeed, California has instituted such a tracking requirement pursuantto Cal. Bus. & Prof. Code §4034(d), and stating a “pedigree shall trackeach dangerous drug at the smallest package or immediate containerdistributed by the manufacturer, received and distributed by thewholesaler, and received by the pharmacy or another person furnishing,administering, or dispensing the dangerous drug”. Also, in a news reportfound in Generics Bulletin, 2 May 2008 page 7 entitled, “US Aims forFederal Track-and-Trace Route”, legislation has been proposed (HR5839Safeguarding America's Pharmaceuticals Act) which “will requirepedigrees on all prescription medicines sold in the US”. The Act, ifenacted, “will require manufacturers, distributors and pharmacies to putin place systems and technologies that will electronically track andtrace individual prescription medicines”.

European Patent Application 137600 [Stuart et al.; filed Jul. 19, 1984;now withdrawn], which is incorporated herein by reference, entitled“Pharmaceutically Active Salts of Morphine” asserts the preparation ofmorphine pamoate salts as the mono-morphine salt and the dimorphine salttrihydrate. The authors further performed pharmacological tests in ratsand humans to compare the effect of morphine pamoate versus morphinesulfate (human tests) or morphine hydrochloride (rats). Within thecontext of the application, morphine pamoate employed in thepharmacological testing was dimorphine pamoate trihydrate, thepreparation of which was described in applicants' Example 1. Inaddition, a reference was cited during the initial examination of theapplication to “morphine pamoate” found in the article “RelationshipBetween In Vitro Dissolution Rates and Solubilities of NumerousCompounds Representative of Various Chemical Species” published in theJournal of Pharmaceutical Sciences, Volume 54, No. 11, November 1965,pp. 1651-53. Incidentally, in this article, no reference was made to thetype of morphine pamoate salt evaluated (mono- or di-morphine salt, orof any polymorphic considerations).

In U.S. Pat. No. 7,201,920 B2 [Kumar et al.], entitled “Method andComposition for Deterring Abuse of Opioid Containing Dosage Forms” theinventors disclose a formulation containing an analgesic and a gelforming polyethylene oxide component and is incorporated herein in itsentirety. The matrix resulting from this and other non-activeingredients (excipients) is intended to result in an abuse resistantformulation.

In U.S. Pat. No. 7,153,966 B2 [Casner et al.], the disclosure of whichis incorporated herein in its entirety, a process is identified for thepreparation of oxycodone possessing very low impurities of14-hydroxycodeinone. Similarly, in US Patent Application Publication US2006/0173029 A1 [Chapman et al.], the disclosure of which isincorporated herein in its entirety, a method is disclosed for preparingoxycodone hydrochloride having less than 25 ppm of 14-hydroxycodeinone.

The control of impurity levels in medicinal opiates continues to receivesignificant inventive attention due to the oversight the US Food andDrug Administration applies to impurities during the drug approvalprocess. US Patent Application Publication US 2008/0132703 A1 [Cox etal.] describes a process for reducing impurities in oxycodone base. InU.S. Pat. No. 6,589,960 B2 [Harclerode et al.] the inventors assert thepreparation of hydromorphone and hydrocodone compositions having novelimpurity profiles. Similarly, in United States Patent ApplicationPublication US 2007/0293676 A1 [Antoninin] describes a method for theseparation and purification of hydrocodone by preparativechromatography. A process for the purification of levorphanol, amorphinan, is described in United States Patent Application PublicationUS 2008/0146805 A1 [Haar et al.] And in U.S. Pat. No. 5,981,751 [Mudryket al.], the inventors describe a process for the removal of residualorganic solvents from various opiate based compounds.

In addition to the impurities contained within a given medicinalproduct, the FDA scrutinizes the polymorphic content of a drug substanceand drug product before market approval is granted. Perhaps as aconsequence of this scrutiny, a series of relevant United States PatentApplication Publications describe various opiate polymorphs, principallythose polymorphs observed as the mineral acid salt. United States PatentApplication Publication US 2007/0197572 A1 [Calderon et al.] describesnine novel polymorphic forms of oxycodone hydrochloride. United StatesPatent Application Publication US 2006/0235039 A1 [Lorimer et al.]describes four novel polymorphic forms of hydromorphone hydrochloride.United States Patent Application Publication US 2007/0072889 A1 [Hagenet al.] describes ten novel forms of hydrocodone bitartrate

Related to the assessment of the polymorphic content of drug substances,the preparation, characterization and utility of pharmaceuticalco-crystals is emerging as a new approach to imparting unique physicaland chemical properties to drug substances. In an article, “Diversity inSingle- and Multiple-Component Crystals; The Search for and Prevalenceof Polymorphs and Cocrystals, published in Crystal Growth & Design,Volume 7, Number 6, 2007, pp. 1007-1026, the author, G. Patrick Stahly,provides an excellent overview of techniques used in polymorph andco-crystal screening. The investigation of cocrystals is wellexemplified in United States Patent Application Publication US2008/016772 A1 [Zaworotko et al.] wherein the solid-sate synthesis ofimides and imines using cocrystals is described.

In a Mar. 29, 2005 report by Dr. William K. Schmidt of Renovis, Inc. theauthor provides an excellent summation of the approaches employed toimpart abuse resistance to controlled substances. This often citedreport can be found at http://www.thci.org/opioid/mar05docs/schmidt.pdfor at http://www.thci.org/opioid/documents/schmidt.pdf. Four approachcategories were identified along with the companies pursuing a technicalimplementation strategy for that approach. These four categories and theassociated companies are listed below. Additional companies have beenadded to the original Schmidt report to represent the currentcontributions and understandings within the industry.

Category 1 Approach: Modified release to resist crushing/extractionCompanies: Collegium, Pain Therapeutics (Durect and KingPharmaceuticals), Roxane (Boehringer Ingelheim), TheraQuest, AcuraPharmaceuticals, Intellipharmaceutics Corporation

Category 2 Approach: Prodrugs

Company: New River Pharmaceuticals (purchased by Shire Pharmaceuticals)

Category 3 Approach: Agonist and antagonist combinations

Companies: Elite, Endo, Purdue Pharma (Euro-Celtique), and 3M

Category 4 Approach: Nasal gel

Company: Ionex Pharmaceuticals (purchased by Vernalis)

With the exception of the prodrug approach, the remaining threecategories rely upon a formulation technique to impart anti-abusefeatures to the drug product and consequently, the four categories citedare essentially equivalent to the three classical approaches describedin the Background of the Invention. Therefore, to fully recognize thescope and benefit of the present invention it is useful to contrast andcompare the prior art generated by the above listed companies to theinventive disclosure herein.

For clarification, each category above is described briefly for thebenefit of those unfamiliar with the techniques used by persons abusingdrug products. First, the GAO report cited herein describes thecrushing/extraction mechanism used by people intent on abusing drugs.Crushing the final dose product can allow for the “liberation” of thecontrolled substance and defeat any controlled release benefit theformulated drug product may have provided. Without the controlledrelease property, the full effect of the active ingredient may be feltby the abuser. Similarly, dissolving the formulated drug product in anappropriate solvent and isolating the active ingredient allows for theanti-abuse property to be circumvented. Hence, methods which defeatcrushing or extraction impart an anti-abuse property to the drugproduct.

Indeed, formulation techniques in conjunction with final dosemanufacturing technologies have been the mainstay for the production ofanti-abuse opioid containing drug products. The approach was to employingredients and coatings technologies to modify the behavior of theopioid API, usually available as it's highly water soluble, mineral acidsalt or as its small organic acid salt yielding similar solubilityproperties. Such approaches to anti-abuse formulations are welldocumented in U.S. Pat. No. 6,103,261 [Chasin et al.] assigned to PurduePharma and entitled “Opioid Formulations Having Extended ControlledRelease”, the disclosure of which is incorporated herein in itsentirety. The literature cited within the '261 patent also provides asignificant foundation to the formulation approach to extended andcontrolled release formulations. The inventors claim a solid oral dosageform of an analgesic compound contained in a controlled release matrixand assert its kinetic release as a function of pH and time as measuredby a specific method. In a similar vein, U.S. Pat. No. 6,245,357 B1[Edgren et al.], incorporated herein by reference in its entirety,describes a sustained release dosage form comprising a drug surroundedby an interior and an exterior wall with an exit for administering thedrug to a patient. The pH independent release of drug productsconsistent with the compartmentalization principles of medicinalchemistry led to U.S. Pat. No. 6,150,410 [Eng et al.] entitled “pHIndependent Extended Release Pharmaceutical Formulation”, the disclosureof which is incorporated herein by reference in its entirety, whereinwater swellable and acid-soluble polymers in conjunction with pre-tabletgranulation methodologies provide unit dosage forms with the titledproperties. Besides controlling the extraction and/or release propertiesof the drug substance from a dosage form by employing extended releaseproperties, dose dumping has also been addressed using formulationtechniques. For purposes herein, dose dumping is defined as the,intentional or unintentional, ethanol accelerated phenomenon in whichthe active pharmaceutical ingredient may be more rapidly released fromthe dosage form than intended and thereby creating a safety risk and/orthe enablement of drug abuse. US Patent Application Publication2007/0212414 A1 [Baichal et al.] entitled “Ethanol Resistant SustainedRelease Formulations”, describes sustained release delivery systemsemploying hetero- and homo-polysaccharide gums, said systems inhibitingdose dumping of a selected opioid. Finally, in relation to formulationand manufacturing technologies, U.S. Pat. No. 6,419,960 [Krishnamurthyet al.] entitled “Controlled Release Formulation Having Rapid Onset andRapid Decline of Effective Plasma Drug Concentrations”, the disclosureof which is incorporated herein in its entirety, describes a formulationsimultaneously exhibiting immediate release and controlled releaseproperties and employing enteric coating manufacturing technology toachieve same.

In regard to the prodrug approach, release is dependent on biochemicalin situ enzymatic cleavage of a covalently bound protecting group or ingeneral, an enzymatic transformation of the prodrug is required in orderto produce the pharmaceutically active compound (or subsequently, ametabolite) that exhibits the desired biological activity. The prodrugconcept as an anti-abuse mechanism is predicated on the belief that the“protected” pharmaceutical active ingredient is otherwise unavailablefor abuse (i.e. in vitro manipulation to yield the active ingredient).The in vivo results from prodrug approaches demonstrate limitations aswell. For instance the drug product, Vyvanse™, containing the prodruglisdexamphetamine dimesylate, exhibits incomplete in vivo removal of theprotecting group as indicated by lisdexamphetamine found in the urine,as reported in the FDA's Drug Approval Package, Clinical Pharmacologyassessment for Vyvanse™ found at the following website:(http://www.fda.gov.cder/foi/nda/2007/021977s000TOC.htm).

The agonist/antagonist approach is constructed around the ability tosequester an antagonist within an agonist product formulation. In theevent that the product formulation is employed in a manner inconsistentwith it's intended route of administration, the antagonist is releaseddefeating the anticipated effect from the agonist. With the nasal gellisted in Schmidt's report, the analgesic buprenorphine is formulatedfor fast effective delivery of the opioid so an anti-abuse productfeature is absent perhaps explaining the observation that onlysublingual product presentations have been approved in the US inconjunction with Vernalis' partner, Reckitt Benckiser.

In regard to Collegium's effort to impart anti-abuse properties tocontrolled substances, an abuse-deterrent pharmaceutical composition isdescribed in United States Patent Application Publication Number US2004/0052731 A1 [Hirsh et al.], the disclosure of which is incorporatedherein in its entirety. The publication indicates the intention to alterthe lipophilicity of an opioid drug substance by complexation witholeophilic metal salts such as zinc stearate. It is suggested that the“likelihood of improper administration of drugs, especially drugs suchas opioids” would be due to the increase in lipophilicity imparted tothe opioid by the complexation.

Another version of the modified release approach to resistcrushing/extraction and to impart abuse deterrence to a drug formulationis summarized in the following information found on Durect's web site:

“The ORADUR Technology is the basis of Remoxy, a novel long-acting oralformulation of the opioid oxycodone which is targeted to decrease thepotential for oxycodone abuse. In December 2007, Remoxy successfullycompleted a pivotal Phase III study. Pain Therapeutics has stated thatit anticipates filing the NDA for Remoxy in the second quarter of 2008.We also have a second ORADUR abuse-resistant opioid product in the PainTherapeutics alliance, about which Pain Therapeutics has announcedpositive results from a Phase I clinical trial.”

Durect is the assignee of U.S. Pat. No. 7,074,803 B2 [Litmanovitz etal.], the disclosure of which is incorporated herein in its entirety.The inventors describe a means of preparing high concentration opioidformulations suitable for use in gel caps. Interestingly, PainTherapeutics (mentioned on Durect's website), is the assignee for U.S.Pat. No. 6,765,010, the disclosure of which is incorporated herein inits entirety, describes the use of opioid receptor antagonists in theformulation of tramadol to enhance the analgesic potency of tramadolwhile mitigating undesired side effects.

Further formulation techniques included those described in United StatesPatent Application Publication 2003/0118641 A1 [Maloney et al.], whichdescribes a method of combining a therapeutically effective amount ofthe opioid compound, or a salt thereof, with a matrix-forming polymerand an ionic exchange resin. The inventors assert this combinationreduces the abuse potential employing extraction techniques of an oraldosage form of an opioid.

The following information was obtained from TheraQuest's website,http://www.theraquestinc.com/pain/abuse.htm, however no related patentsor published patent applications have been identified. TheraQuestdescribes another formulation technique to impart anti-abuse propertiesto drug products. Stated therein is:

“TheraQuest's Abuse Deterrent SECUREL™ Technology

Toxicity from high blood levels of sustained release opioids and otherabusable drugs often occurs when recreational drug users and addictscrush the contents of the tablet or capsule and ingest the drug orally,snort it or inject it intravenously, after extraction and filtration.TheraQuest has developed a proprietary secure-release (SECUREL™) abusedeterrent sustained release oral drug delivery platform. SECUREL™operates by resisting crushing, melting and both chemical and physicalattempts to extract the abusable drug. SECUREL™ formulations aredifficult to tamper with and are designed to form a viscous substanceupon contact with a solvent, such that the abusable drug cannot beeasily filtered or drawn into a syringe for intravenous drug abuse. Theyare also resistant to extraction with common solvents, includingalcohol. A potential advantage of such a “passive” abuse deterrentsystem is that it may protect both medical and non-medical users ofopioids and other abusable drugs from intentional or unintentionalopioid toxicity, without unnecessary harm to either group from the abusedeterrent technology.”

In U.S. Pat. No. 7,201,920 B2 [Kumar et al.] assigned to AcuraPharmaceuticals, the disclosure of which is incorporated herein in itsentirety, the inventors describe a formulation technique to prepareabuse deterrent dosage forms of opioid analgesics by employing apolyethylene oxide polymer to form a matrix.

In March 2008, Intellipharmaceutics reported the successful completionof a pilot clinical trial for its abuse and alcohol resistant sustainedrelease oxycodone. From their website, www.intellipharmaceuitcs.com, thecompany reports as excerpted below:

“Mar. 27, 2008—IntelliPharmaCeutics Ltd. (Delaware) is pleased toannounce significant results from a recently completed pilot clinicaltrial for its new abuse-resistant, alcohol-resistant once-a-day oraloxycodone formulation by its operating company IntelliPharmaCeuticsCorp. of Toronto (“IntelliPharmaCeutics” or the “Company”). The productis covered by pending patent applications for its novel ReXista™ abuseand alcohol resistant drug delivery technology. It is one of theCompany's line of in-house analgesic products in development for themanagement of moderate to severe chronic and acute pain.The ReXista™ oxycodone product is a novel dosage form, designed to beresistant to abuse by oral ingestion when crushed or chewed, byinjection when combined with solvents, and by nasal application whencrushed or powdered. The abuse of this important pain relief drug hasbeen well documented over many years.”

Intellipharmaceutics' technology describing the proclaimed attributesthrough formulation is contained in a series of United States Patents,specifically, U.S. Pat. No. 6,676,966 B1 [Odidi et al.], U.S. Pat. No.6,652,882 B1 [Odidi et al.] and U.S. Pat. No. 6,800,668 B1 [Odidi etal.], each incorporated herein in their entirety.

With respect to the prodrug approach to attaining an anti-abuseformulation, New River's efforts at obtaining FDA approval of Vyvanse™was well rewarded by Shire Pharmaceutical's purchase of New River for$2.6 billion. New River's patent U.S. Pat. No. 7,105,486 B2 (Mickle etal.) the disclosure of which is totally incorporated herein byreference, describes the covalent attachment of L-lysine to the drugsubstance, amphetamine, to provide compounds and compositions exhibitingabuse-resistant properties and useful for the treatment of disordersincluding attention deficit hyperactivity disorder (ADHD), attentiondeficit disorder (ADD), narcolepsy and obesity.

Similarly, Buchwald, et al. in United States Patent ApplicationPublication (US 2004/0058946 A1), the disclosure of which is totallyincorporated herein by reference, identifies modified oxycodonederivatives (prodrug) such that its physiological activity is onlyobserved after the prodrug is converted to the drug in the mammaliangastrointestinal tract. Mickle, et al. in United States PatentApplication Publication (US 2005/0266070 A1), the disclosure of which istotally incorporated herein by reference, identifies hydrocodoneconjugates that release the drug substance following oral administrationyet are resistant to intravenous or intranasal abuse.

Category 3 of Schmidt's report describes the industry's efforts toformulate opioid drug products which also contain an antagonist. Theformulation techniques essentially sequester the antagonist so that thedrug product produces the desired pharmaceutical effect when used forits intended purpose. However, should the drug product dosagepresentation undergo manipulation (i.e. crushing or extraction) theantagonist is released and the potential for drug abuse is thwarted.Several companies have pursued this approach. For example, successfulclinical trials were announced by the company Alpharma and reported inFDAnews Drug Pipeline Alert™ (Volume 4, No. 193, Oct. 3, 2006). Thecapsule formulation consists of an extended-release opioid with asequestered core of naltrexone, an opioid antagonist. The sequesteringsubunit enabling this technology is described by Boehm in United StatesPatent Application Publication US 2004/01341552 A1, and is totallyincorporated herein by reference.

Similarly, Elite Pharmaceuticals is reportedly initiating a Phase IIclinical trial of its abuse resistant pain drug also employing theantagonist naltrexone hydrochloride. The report found in FDAnews DrugPipeline Alert™ (Volume 4, No. 179, Sep. 13, 2006) states the previousPhase 1 trial confirmed the technical approach such that when the drugproduct was taken as intended, no antagonist was measured in the bloodstream. However, if the drug product was crushed, the antagonist wasreleased into the blood stream and the euphoria normally experience byoxycodone hydrochloride abusers was reduced.

Not surprisingly, Purdue Pharma (Euro-Celtique) has also pursued theagonist/antagonist combination formulation in an effort to impartanti-abuse properties to opioid analgesics. In U.S. Pat. No. 7,332,182B2 [Sackler], the disclosure of which is incorporated herein in itsentirety, the inventor includes an irritant in the agonist/antagonistopioid formulation to further discourage use of the drug product forreasons other than its intended purpose. U.S. Pat. No. 6,696,066 [Kaikoet al.], the disclosure of which is incorporated herein in its entirety,describes a sustained release agonist/antagonist formulation capable ofproducing a mildly negative, “aversive” experience in physicallydependent addicts.

Lastly, in regard to the agonist/antagonist approach to abuse resistantproducts, 3M received U.S. Pat. No. 7,182,955 B2 [Hart et al.], thedisclosure of which is incorporated herein in its entirety, theinventors describe an abuse resistant transdermal dosage form (a patch)formulated and assembled to deliver the desired active agent when theproduct is used in a manner consistent with its intended purpose yetdeliver the antagonist if improperly used.

For the Category 4 approach of the Schmidt report regarding use of anasal gel, Ionix Pharmaceuticals is the assignee of United States PatentApplication Publication 2007/0231269 [Birch et al.] describing the nasaldelivery of an opioid analgesic or a non-steroidal anti-inflammatorydrug in a manner to produce a therapeutic plasma concentration withinthirty minutes with a duration of at least two hours.

Despite the administrative efforts to curtail drug abuse via educationalmaterials, medical professional training, patient counseling, lawenforcement support, drug abuse treatment programs, drug prescribingprotocols, legislative action, public awareness, governmental reporting,medical professional organizations' support of anti-abuse products, andcharitable and religious group influence, and all combinations of theseand other activities, the statistics indicate drug abuse is growing at arate faster than the population's growth. It is clear society hasrecognized and is aware of the consequences of drug abuse and whileadministrative measures may diminish the problem, the financial gainavailable to practitioners of the illicit drug trade likely draw ananalogy to the government's attempt at alcohol prohibition and enactmentof the Eighteenth Amendment. This legislative exercise proved futile andmade many willing participants of the illegal trafficking of alcoholwealthy. Ultimately, the Twenty-First Amendment repealed the VolsteadAct and Prohibition ended. With its end, the financial incentive wasalso removed and alcohol taxation returned. Administrative efforts mayhave little impact on the drug abuse crisis to which the Nation suffersuntil our borders are secured.

In respect to the technical efforts expended to curtail drug abuse,industry icons and small companies alike have instituted research anddevelopment programs at immense expense to identify reliable solutions,through chemistry, to achieve abuse resistant/tamper-proof drugproducts. Unfortunately, the rational approaches to date have met withlimited success and the alternatives require a more extensive andinventive manipulation of the related chemistries—particularly to impartsuch properties to the opioid family of drug products. Described hereinbelow is such an inventive solution to address the need for a platformapproach to introducing anti-abuse properties to controlled substancepharmaceuticals and to other medicinal products which may be abused.

As in the above discussion, administrative and technical measures willbe required to effectively curb drug abuse. The technical contributionshave primarily centered upon formulation technologies to prevent thephysical extraction of the active ingredient from the dosage product.While the formulation approach is valid, it also contains inherent flawssince any pharmaceutical composition relying on physical mixtures and/orthe mixture's differential solubilities and/or other physical/mechanicalbarriers (e.g. a matrix) to impart anti-abuse properties can be overcomeemploying physical means. Fundamentally, these various formulationtechniques would provide excellent second-line defense mechanisms whencoupled with a chemical methodology to impart anti-abuse properties tothe drug product. By way of example, with the aforementioned prodrugdiscussion regarding the amphetamine exemplar embodied in New River'sVyvanse™, the drug product delivers an anti-abuse feature throughchemical means which would be very difficult to defeat—and only throughchemical transformation. Unfortunately, the prodrug approach, ingeneral, requires significant R&D resources to tailor each prodrug to ahost of regulatory specifications before market approval can be grantedby the FDA. Consequently, the prodrug approach is costly, time-intensiveand does not provide a universal, platform solution to impartinganti-abuse properties to the medially necessary amine-containingcontrolled substances. The invention described herein encompasses aplatform approach to imparting anti-abuse properties at the molecularlevel through unique salt forms of the opioid alkaloids.

In spite of the ongoing, and extensive, efforts there is still andstrong, even mandated, desire for an opioid which is less susceptible topurposeful or incendental abuse particularly with regards to dosedumping.

SUMMARY OF THE INVENTION

The present invention provides the ability to modify the dissolutionperformance features of narcotics, and in particular, opiates by thedesign and selection of the opiate as an organic acid addition salt.Five design factors are relevant: 1) the hydrophilicity of the opioid,2) the family of organic acid selected for forming the organic acidaddition salt with the amine-containing opiate, 3) the relativestoichiometry available between the amine-containing opiate and thenumber of salt forming sites on the organic acid component, 4) theselection of an amorphous, polymorphic or combinations thereof of theorganic acid addition salt of the amine-containing opiate, and 5) theemployment of an additional organic acid (or its non-active ingredientsalt) as a functional excipient. For purposes herein, a functionalexcipient is defined as an otherwise pharmaceutically inert material butwhen employed with the active pharmaceutical ingredient salts describedherein, a synergistic effect is obtained wherein the excipientcontributes to the performance features desired which is inhibition ofdose dumping. These five factors may be used individually or incombination with one another, and/or employed in concert with existingformulation techniques to provide drug product formulations exhibitinganti-abuse features and/or to provide modified dissolution profiles ascompared singularly to the opiate mineral acid salt.

One embodiment of the present invention comprises organic acid additionsalts of the amine containing opioid family of narcotic compoundscomprising opiates of natural product isolates, natural isolates furtherprocessed by synthetic or enzymatic processes, and lastly, thosecompounds possessing structural characteristics similar to the naturalopiates yet obtained completely from synthetic processes, and theprocesses thereof for their manufacture. The compounds of interestinclude but are not limited to oxycodone, hydrocodone, morphine,apomorphine, hydromorphone, oxymorphone, codeine, dihydrocodeine,codeinone, thebaine, morphothebaine, thebenine, metathebainone,phenyldihydrothebaine, thebainhydroquinone, flavothebanone,alpha-codeimethine, acetylmethylmorphol, methylmorphenol,14-hydroxycodeinone, sinomenine, dihydrosinomenine, hasubanonine,levorphanol, nalbuphine, nalmefene, naloxone, naltrexone, noscapine,opium, and oripavine. While structurally similar, these compoundsrepresent a range of hydrophilic character predominantly driven by thepresence of oxygen-containing functionality (ketone, aryl ether,ring-fused/cyclic aryl-alkyl ether, phenol, primary and secondaryalcohol). The hydrophilic character of these opioids and their abilityto hydrogen bond with water and alcohols facilitates their ability to beextracted from, and analogously, to be susceptible to dose dumping froma formulated product.

Consequently, it is an object of the present invention to temporarilyinterrupt the hydrophilic behavior of an opioid or opioids bypreparation of its organic acid addition salt such that extraction ordose dumping of the opioid occurs principally in the gastrointestinaltract (human or animal) and in a relevant time frame for therapeutictreatment. Further, the selection of a particular organic acid additionsalt for a given opiate is selected based upon the kinetics ofdissolution wherein only about 0-80% of the opiate is released from itssalt form over a period of about 60-90 minutes while in the presence ofabout 0-40% alcohol.

It is an object of the present invention to provide organic acidaddition salts of opioid amine-containing compounds which exhibitanti-abuse properties providing for bio-availability of the drugsubstance when the drug product is used in a manner consistent with itsintended route of administration, but which is otherwise bio-unavailableif used by an unintended route of administration.

It is an object of the present invention to impart unique anti-dosedumping properties to alkaloids by preparation of their amorphous andpolymorphic organic acid addition salts and formulations therewith.

It is an object of this invention to engineer into, or tailor, thedissolution profiles of the organic acid addition salts of opioidamine-containing compounds by employing at least one of the followingfactors: a) selection of an organic acid family selected from the groupof pamoates, xinafoates or salicylates, b) selection of an availablestoichiometric relationship between the amine and the organic acidfamily, c) selection of a particular polymorph, or combinations orpolymorphs, each with or without amorphous content and each with orwithout solvent inclusion such as hydrates or solvates, and d)formulation of the organic acid salt of the opioid with additionalquantities of an organic acid or its non-API salt such as formulationwith pamoic acid, disodium pamoate, beta-hydroxynaphthoic acid itsisomers and inorganic salts.

It is an object of the present invention to provide organic acidaddition salts of opioid compounds which are resistant to and inhibitdose dumping.

It is an object of the present invention to provide formulationscomprising an organic acid or its non-API salt such as formulation withpamoic acid, disodium pamoate, beta-hydroxynaphthoic acid its isomersand inorganic salts to impart an anti-dose-dumping feature to a drugproduct formulation.

It is an object of the present invention to provide organic acidaddition salts of opioid compounds similar in structure to the followingsubstituted morphinans and to opiates in general, for example but notlimited to that of morphine:

It is an object of the present invention to provide organic acidaddition salts of opioid compounds selected from the group consisting ofbut not limited to oxycodone, hydrocodone, morphine, apomorphine,hydromorphone, oxymorphone, codeine, dihydrocodeine, codeinone,thebaine, morphothebaine, thebenine, metathebainone,phenyldihydrothebaine, thebainhydroquinone, flavothebanone,alpha-codeimethine, acetylmethylmorphol, methylmorphenol,14-hydroxycodeinone, sinomenine, dihydrosinomenine, hasubanonine,levorphanol, nalbuphine, nalmefene, naloxone, naltrexone, noscapine,opium, and oripavine, their (bio)-synthetic intermediates and syntheticderivatives.

It is an object of the present invention to provide organic acidaddition salts of opioid compounds wherein the organic acid componentdefined as Structure A further herein.

It is a feature of the present invention that the organic acid additionsalts of the opioid family of alkaloids are available in amorphous andpolymorphic forms, said amorphous and polymorphic forms havingunexpectedly low phase transitions for the amorphous form andsignificantly high phase transitions for the polymorphic form.

It is a feature of the present invention that the amorphous andpolymorphic forms of the organic acid addition salts of the opioidfamily of alkaloids exhibit unexpectedly high enthalpies of phasetransition.

A particular feature of the present invention is that the amorphous andpolymorphic forms of the organic acid addition salts of the opioidfamily of alkaloids exhibit essentially identical dissolution rates.

A feature of the present invention is robust and stable drug productformulations prepared from the organic acid addition salts of the opioidfamily of alkaloids.

It is yet another feature of the present invention to provide tamperresistant and/or tamper proof drug product formulations employing theorganic acid addition salts of the opioid family of alkaloids.

It is another feature of the present invention to provide organic acidaddition salts of the opioid family of alkaloids which when employedwith an anti-abuse formulation technique impart at least two anti-abusemechanisms into the drug product.

It is a feature of the present invention to employ physical and chemicalmeans to prepare anti-abuse controlled substance formulations.

Another feature of the invention described herein is the synergisticeffect observed for reducing dose dumping when formulating opioidorganic acid addition salts with an excess of the specific acidcomponent or selected from the group of organic acids impartinganti-abuse properties and whereas in the acid component or those of thegroup may be employed as their alkali metal salt.

These and other advantages, as will be realized, are provided in a drugsubstance with a pharmaceutically acceptable organic acid addition saltof an opioid wherein said organic acid is selected from Structure A:

wherein R¹-R⁴ are independently selected from H, alkyl or substitutedalkyl of 1-6 carbons, adjacent groups may be taken together to form acyclic alkyl, cyclic alkyl-aryl, or cyclic aryl moiety;R⁵ is selected from H, or an alkali earth cation;R⁶ and R⁷ are independently selected from H, alkyl of 1-6 carbons, analkali earth cation, and aryl of 6 to 12 carbons, in a number sufficientto complete the valence bonding of X, andwherein X is selected from nitrogen, oxygen or sulfur; andwherein the drug substance has a morphology selected from amorphous andcrystalline.

Another embodiment is provided in a method for mitigating dose dumpingcomprising providing a drug product comprising a drug substance whereinthe drug substance comprises an opioid wherein the opioid has a wt %released at 30 minutes in 0.1 N hydrochloric acid comprising ethanolwhich is no higher than in 0.1 N hydrochloric acid without ethanol.

Yet another embodiment is provided in a drug product which is notsusceptible to dose dumping wherein the drug product comprises a drugsubstance comprising an opioid wherein the opioid has a wt % released at30 minutes in 0.1 N hydrochloric acid comprising ethanol which is nohigher than in 0.1 N hydrochloric acid not comprising ethanol.

Yet another embodiment is provided in a drug product comprising a drugsubstance comprising a pharmaceutically acceptable organic acid additionsalt of an opioid wherein the organic acid is selected from Structure A:

wherein R¹-R⁴ are independently selected from H, alkyl or substitutedalkyl of 1-6 carbons, adjacent groups may be taken together to form acyclic alkyl, cyclic alkyl-aryl, or cyclic aryl moiety;R⁵ is selected from H, or an alkali earth cation;R⁶ and R⁷ are independently selected from H, alkyl of 1-6 carbons, analkali earth cation, and aryl of 6 to 12 carbons, in a number sufficientto complete the valence bonding of X, andwherein X is selected from nitrogen, oxygen or sulfur andwherein less than 85 wt % of said opioid is released at a biological pHin 1 hour.

Yet another embodiment is provided in a drug product which is notsusceptible to dose dumping comprising a pharmaceutically acceptableorganic acid addition salt of an opioid wherein said organic acid isselected from Structure A:

wherein R¹-R⁴ are independently selected from H, alkyl or substitutedalkyl of 1-6 carbons, adjacent groups may be taken together to form acyclic alkyl, cyclic alkyl-aryl, or cyclic aryl moiety;R⁵ is selected from H, or an alkali earth cation;R⁶ and R⁷ are independently selected from H, alkyl of 1-6 carbons, analkali earth cation, and aryl of 6 to 12 carbons, in a number sufficientto complete the valence bonding of X, andwherein X is selected from nitrogen, oxygen or sulfur; anda material defined by Structure H:

wherein R⁸-R⁹ are independently selected from H, alkyl or substitutedalkyl of 1-6 carbons, adjacent groups may be taken together to form acyclic alkyl, cyclic alkyl-aryl, or cyclic aryl moiety;R¹² is selected from H, or an alkali earth cation;R¹³ and R¹⁴ are independently selected from H, alkyl of 1-6 carbons, analkali earth cation, and aryl of 6 to 12 carbons, in a number sufficientto complete the valence bonding of X, andwherein X is selected from nitrogen, oxygen or sulfur andwherein said opioid has a wt % released at 30 minutes in 0.1 Nhydrochloric acid comprising ethanol which is no higher than in 0.1 Nhydrochloric acid not comprising ethanol.

Yet another embodiment is provided in a method of administering anactive pharmaceutical comprising providing an opioid containingpharmaceutically active compound in a dose suitable for achieving atherapeutic dose of said opioid in a predetermined time wherein saidtherapeutic dose is not exceeded by ingestion of alcohol at biologicalpH.

A solid, controlled release, oral dose form of an active pharmaceuticalwherein said dose form comprises an analgesically effective amount of anopioid salt wherein at least 12.5 wt % to no more than 42.5 wt % of saidopioid is bioavailable at 1 hour at a biological pH and wherein saidopioid bioavailability is not increased in the presence of ingestedalcohol.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is the differential scanning calorimetry (DSC) thermogram ofamorphous oxycodone pamoate.

FIG. 2 is the Fourier Transform Infrared (FTIR) spectrum of amorphousoxycodone pamoate.

FIG. 3 is the powder X-ray diffraction (PXRD) diffractogram of amorphousoxycodone pamoate.

FIG. 4 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic oxycodone pamoate.

FIG. 5 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicoxycodone pamoate.

FIG. 6 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic oxycodone pamoate.

FIG. 7 is the differential scanning calorimetry (DSC) thermogram ofoxycodone xinafoate.

FIG. 8 is the Fourier Transform Infrared (FTIR) spectrum of oxycodonexinafoate.

FIG. 9 is the powder X-ray diffraction (PXRD) diffractogram of oxycodonexinafoate.

FIG. 10 is the differential scanning calorimetry (DSC) thermogram ofamorphous hydrocodone pamoate.

FIG. 11 is the Fourier Transform Infrared (FTIR) spectrum of amorphoushydrocodone pamoate.

FIG. 12 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous hydrocodone pamoate.

FIG. 13 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic hydrocodone pamoate.

FIG. 14 is the Fourier Transform Infrared (FTIR) spectrum of polymorphichydrocodone pamoate.

FIG. 15 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic hydrocodone pamoate.

FIG. 16 is the differential scanning calorimetry (DSC) thermogram ofhydrocodone xinafoate.

FIG. 17 is the Fourier Transform Infrared (FTIR) spectrum of hydrocodonexinafoate.

FIG. 18 is the powder X-ray diffraction (PXRD) diffractogram ofhydrocodone xinafoate.

FIG. 19 is the differential scanning calorimetry (DSC) thermogram ofamorphous hydromorphone pamoate.

FIG. 20 is the Fourier Transform Infrared (FTIR) spectrum of amorphoushydromorphone pamoate.

FIG. 21 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous hydromorphone pamoate.

FIG. 22 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic hydromorphone pamoate.

FIG. 23 is the Fourier Transform Infrared (FTIR) spectrum of polymorphichydromorphone pamoate.

FIG. 24 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic hydromorphone pamoate.

FIG. 25 is the differential scanning calorimetry (DSC) thermogram ofhydromorphone xinafoate.

FIG. 26 is the Fourier Transform Infrared (FTIR) spectrum ofhydromorphone xinafoate.

FIG. 27 is the powder X-ray diffraction (PXRD) diffractogram ofhydromorphone xinafoate.

FIG. 28 is the differential scanning calorimetry (DSC) thermogram ofamorphous morphine pamoate.

FIG. 29 is the Fourier Transform Infrared (FTIR) spectrum of amorphousmorphine pamoate.

FIG. 30 is the powder X-ray diffraction (PXRD) diffractogram ofamorphous morphine pamoate.

FIG. 31 is the differential scanning calorimetry (DSC) thermogram ofpolymorphic morphine pamoate.

FIG. 32 is the Fourier Transform Infrared (FTIR) spectrum of polymorphicmorphine pamoate.

FIG. 33 is the powder X-ray diffraction (PXRD) diffractogram ofpolymorphic morphine pamoate.

FIG. 34 is the differential scanning calorimetry (DSC) thermogram ofmorphine xinafoate.

FIG. 35 is the Fourier Transform Infrared (FTIR) spectrum of morphinexinafoate.

FIG. 36 is the powder X-ray diffraction (PXRD) diffractogram of morphinexinafoate.

FIG. 37 is the graphical representation of the dissolution profiles foroxycodone hydrochloride as a function of pH.

FIG. 38 is the graphical representation of the dissolution profiles foramorphous oxycodone pamoate as a function of pH.

FIG. 39 is the graphical representation of the dissolution profiles forpolymorphic oxycodone pamoate as a function of pH.

FIG. 40 is the graphical representation of the dissolution profiles fora formulation (2:1 molar) of oxycodone hydrochloride and disodiumpamoate as a function of pH.

FIG. 41 is the graphical representation of the dissolution profiles fora formulation (1:2 molar) of oxycodone hydrochloride and disodiumpamoate as a function of pH.

FIG. 42 is the graphical representation of the dissolution profiles fora formulation (2:1 molar) of oxycodone hydrochloride and pamoic acid asa function of pH.

FIG. 43 is the graphical representation of the dissolution profiles fora formulation (1:2 molar) of oxycodone hydrochloride and pamoic acid asa function of pH.

FIG. 44 is the graphical representation of the dissolution profiles fora formulation (1:1:1 molar) of oxycodone hydrochloride, disodium pamoateand pamoic acid as a function of pH.

FIG. 45 is the graphical representation of the dissolution profiles fora formulation (2:1 molar) of oxycodone free base and pamoic acid as afunction of pH.

FIG. 46 is the graphical representation of the dissolution profiles fora formulation (1:1 molar) of amorphous oxycodone pamoate and disodiumpamoate as a function of pH.

FIG. 47 is the graphical representation of the dissolution profiles fora formulation (1:1 molar) of amorphous oxycodone pamoate and pamoic acidas a function of pH.

FIG. 48 is the graphical representation of the dissolution profiles fora formulation (1:1 molar) of polymorphic oxycodone pamoate and disodiumpamoate as a function of pH.

FIG. 49 is the graphical representation of the dissolution profiles foramorphous hydrocodone pamoate as a function of pH.

FIG. 50 is the graphical representation of the dissolution profiles forpolymorphic hydrocodone pamoate as a function of pH.

FIG. 51 is the graphical representation of the dissolution profiles forhydrocodone xinafoate as a function of pH.

FIG. 52 is the graphical representation of the dissolution profiles foramorphous hydromorphone pamoate as a function of pH.

FIG. 53 is the graphical representation of the dissolution profiles forpolymorphic hydromorphone pamoate acetone solvate as a function of pH.

FIG. 54 is the graphical representation of the dissolution profiles forhydromorphone xinafoate as a function of pH.

FIG. 55 is the graphical representation of the dissolution profiles foramorphous morphine pamoate as a function of pH.

FIG. 56 is the graphical representation of the dissolution profiles forpolymorphic morphine pamoate acetone solvate as a function of pH.

FIG. 57 is the graphical representation of the dissolution profiles formorphine xinafoate as a function of pH.

FIG. 58 is the graphical representation of the dissolution profiles foroxycodone hydrochloride as a function of ethanol concentration.

FIG. 59 is the graphical representation of the dissolution profiles foroxycodone hydrochloride in acidic media as a function of ethanolconcentration.

FIG. 60 is the graphical representation of the dissolution profiles fora formulation (1:1 molar) of oxycodone hydrochloride and disodiumpamoate in acidic media as a function of ethanol concentration.

FIG. 61 is the graphical representation of the dissolution profiles ofamorphous oxycodone pamoate as a function of ethanol concentration.

FIG. 62 is the graphical representation of the dissolution profiles foramorphous oxycodone pamoate in acidic media as a function of ethanolconcentration.

FIG. 63 is the graphical representation of the dissolution profiles foramorphous oxycodone pamoate in acidic media as a function of ethanolconcentration.

FIG. 64 is the graphical representation of the dissolution profiles fora formulation (1:1 molar) of amorphous oxycodone pamoate and disodiumpamoate in acidic media as a function of ethanol concentration.

FIG. 65 is the graphical representation of the dissolution profiles ofpolymorphic oxycodone pamoate in acidic media as a function of ethanolconcentration.

FIG. 66 is the graphical representation of the dissolution profiles fora formulation (1:1 molar) of polymorphic oxycodone pamoate and disodiumpamoate in acidic media as a function of ethanol concentration.

FIG. 67 is the graphical representation of the dissolution profiles foroxycodone xinafoate in acidic media as a function of ethanolconcentration.

FIG. 68 is the graphical representation of the dissolution profilesoxycodone xinafoate as a function of pH.

FIG. 69 is the graphical representation of the dissolution profiles fora formulation (2:1 molar) of oxycodone hydrochloride and disodiumpamoate in acidic media as a function of ethanol concentration.

FIG. 70 is the graphical representation of the dissolution profiles of aformulation (1:1 molar) of oxycodone hydrochloride and disodium pamoateas a function of pH.

FIG. 71 is the graphical representation of the dissolution profiles fora formulation (1:2 molar) of oxycodone hydrochloride and disodiumpamoate in acidic media as a function of ethanol concentration.

FIG. 72 is the graphical representation of the dissolution profiles fora formulation (1:2 molar) of oxycodone hydrochloride and pamoic acid inacidic media as a function of ethanol concentration.

FIG. 73 is the graphical representation of the dissolution profiles fora formulation (1:2 molar) of amorphous oxycodone pamoate and disodiumpamoate in acidic media as a function of ethanol concentration.

FIG. 74 is the graphical representation of the dissolution profiles fora formulation (1:2) molar of amorphous oxycodone pamoate and3-hydroxy-2-naphthoic acid (BON Acid) as a function of pH.

FIG. 75 is the graphical representation of the dissolution profiles fora formulation (1:2 molar) of polymorphic oxycodone pamoate and disodiumpamoate as a function of pH.

FIG. 76 is the graphical representation of the dissolution profiles fora formulation (1:1 molar) of polymorphic oxycodone pamoate with pamoicacid in acidic media as a function of ethanol concentration.

FIG. 77 is the graphical representation of the dissolution profiles of aformulation (1:2 molar) of polymorphic oxycodone pamoate with3-hydroxy-2-naphthoic acid (BON acid) in acidic media as a function ofethanol concentration.

FIG. 78 is the graphical representation of the dissolution profiles ofhydrocodone bitartrate as a function of pH.

FIG. 79 is the graphical representation of the dissolution profiles ofhydrocodone bitartrate in acidic media as a function of ethanolconcentration.

FIG. 80 is the graphical representation of the dissolution profiles of aformulation (1:2) molar of hydrocodone bitartrate and3-hydroxy-2-naphthoic acid (BON Acid) as a function of pH.

FIG. 81 is the graphical representation of the dissolution profiles of aformulation (1:2 molar) of hydrocodone bitartrate and3-hydroxy-2-naphthoic acid (BON Acid) in acidic media as a function ofethanol concentration.

FIG. 82 is a graphical representation of the dissolution profiles ofhydrocodone xinafoate in acidic media as a function of ethanolconcentration.

FIG. 83 is a graphical representation of the dissolution profiles of aformulation (1:2 molar) of hydrocodone xinafoate and3-hydroxy-2-naphthoic acid (BON acid) as a function of pH.

FIG. 84 is a graphical representation of the dissolution profiles of aformulation (1:2 molar) of hydrocodone xinafoate and3-hydroxy-2-naphthoic acid (BON acid) in acidic media as a function ofethanol concentration.

FIG. 85 is a graphical representation of the dissolution profiles of aformulation (2:1 molar) of amorphous oxycodone pamoate and disodiumpamoate in acidic media as a function of ethanol concentration.

FIG. 86 is a graphical representation of the dissolution profiles of aformulation (2:1) molar of polymorphic oxycodone pamoate and disodiumpamoate in acidic media as a function of ethanol concentration.

FIG. 87 is a graphical representation of the dissolution profiles ofamorphous hydrocodone pamoate in acidic media as a function of ethanolconcentration.

FIG. 88 is a graphical representation of the dissolution profiles ofamorphous hydrocodone pamoate acetone solvate as a function of pH.

FIG. 89 is a graphical representation of the dissolution profiles ofamorphous hydrocodone pamoate acetone solvate in acidic media as afunction of ethanol concentration.

FIG. 90 is a graphical representation of the dissolution profiles ofhydromorphone hydrochloride as a function of pH.

FIG. 91 is the graphical representation of the dissolution profiles ofhydromorphone hydrochloride in acidic media as a function of ethanolconcentration.

FIG. 92 is a graphical representation of the dissolution profiles ofamorphous hydromorphone pamoate in acidic media as a function of ethanolconcentration.

FIG. 93 is a graphical representation of the dissolution profiles ofpolymorphic hydromorphone pamoate acetone solvate in acidic media as afunction of ethanol concentration.

FIG. 94 is a graphical representation of the dissolution profiles ofmorphine sulfate as a function of pH.

FIG. 95 is a graphical representation of the dissolution profiles ofpolymorphic morphine pamoate acetone solvate in acidic media as afunction of ethanol concentration.

FIG. 96 is a graphical representation of the dissolution profiles ofoxycodone pamoate in a 2^(nd) polymorphic form as a function of pH.

FIG. 97 is a graphical representation of the dissolution profiles ofoxycodone pamoate in a 2^(nd) polymorphic form in acidic media as afunction of ethanol concentration.

FIG. 98 is the differential scanning calorimetry (DSC) thermogram ofoxycodone pamoate in a 2^(nd) polymorphic form.

FIG. 99 is the Fourier Transform Infrared (FTIR) spectrum of oxycodonepamoate in a 2^(nd) polymorphic form.

FIG. 100 is the Powder X-Ray Diffraction (PXRD) diffractogram ofoxycodone pamoate in a 2^(nd) polymorphic form.

FIG. 101 is the Nuclear Magnetic Resonance (NMR) spectrum of oxycodonepamoate in a 2^(nd) polymorphic form.

FIG. 102 is the graphical representation of the dissolution profiles ofimipramine hydrochloride as a function of pH.

FIG. 103 is the graphical representation of the dissolution profiles ofimipramine hydrochloride in acidic media as a function of ethanolconcentration.

FIG. 104 is the graphical representation of the dissolution profiles ofimipramine pamoate as a function of pH.

FIG. 105 is the graphical representation of the dissolution profiles ofimipramine pamoate in acidic media as a function of ethanolconcentration.

DETAILED DESCRIPTION OF THE INVENTION

A pharmaceutical formulation is provided which is particularlyadvantageous with regards to patient safety is described herein. Theformulation comprises a salt of an opioid wherein the salt prohibits theopioid from being susceptible to abuse particularly with regards to dosedumping.

Particularly preferred for the present application are morphinans,synonymous herein with the term opioids, with hydrocodone, oxycodone,hydromorphone and morphine being most preferred. Together these opioidsrepresent a range of potential chemical and physical phenomenapertaining to opioid hydrophilicity as a class. Indeed, each of theseopioids as their hydrochloride salt exhibit good solubility in water asexpected. However, to demonstrate the depth and breadth of the presentinvention, the degree of hydrophilicity as determined by hydroxylmoieties on the opioid, was considered as a demonstrative factor for thegeneral applicability of the processes and performance featuresdescribed herein. Specifically, hydrocodone does not contain a hydroxylgroup; oxycodone contains one hydroxyl moiety as a tertiary cyclo-alkylalcohol; hydromorphone contains one phenolic hydroxyl whereas morphinecontains one phenolic hydroxyl and one secondary cyclo-alkyl alcohol.The formation of organic acid addition salts with these compounds wasshown to have a significant impact on their properties such that thetype of salt formed, i.e. of the pamoate or xinafoate families, whencompared with the mineral acid or small organic acid salt such astartrate. Indeed, the hydrophilic nature of the opioids by the presenceof hydroxyl groups would need to be overcome in order to obtainperformance differentiation between the mineral acid salts versus thesalts of the present invention.

In an embodiment of the present invention, the controlled substance isan amine-containing organic salt which does not release in the pH windowof about 4 to about 9. At a pH of less than about 4, the subject organicsalts become protonated with the concomitant precipitation of organicacid. At pH greater than about 9, the addition salt is soluble yet it isquite difficult to distinguish between the organic acid component andthe active amine by organic solvent extraction.

The organic acids of the present invention are those forming salts withamine-containing active pharmaceutical ingredients which preferably donot release in an aqueous solution within a pH window of about 4 toabout 9 and which interfere with the direct isolation of the API outsideof the central pH window.

The organic acid is defined by the following Structures A through Gwherein Structure A represents the general family of Markush compoundsembodied within the invention. Structure B represents the subset ofsalicylic acid and its derivatives conceived as a component of thisinvention. Structures C, D and E are regio-isomeric variations onCompound A wherein two adjacent substituents on Compound A form a fusedaryl ring (i.e. R¹+R²; R²+R³; and R³+R⁴). Structures F and G represent afurther sub-category of dimer-like compounds derived from Structure A.In Structure F, dimerization has occurred through R⁴ of two Structure Acompounds with both possessing fused-aryl ring systems formed via R²+R³.In Structure G, dimerization has again occurred through R⁴ of twoStructure A compounds however both Structure A residues possessfused-aryl ring systems formed via R¹+R².

Wherein R¹-R⁴ are independently selected from H, alkyl or substitutedalkyl of 1-6 carbons, adjacent groups may be taken together to form acyclic alkyl or cyclic aryl moiety; R⁵ represents H, alkyl, alkylacyl orarylacyl; R⁶ and R⁷ are independently selected from H, alkyl of 1-6carbons, aryl of 6-12 carbons, alkylacyl or arylacyl analoguessufficient to satisfy the valence of X (e.g. to provide a mixedanhydride or carbamate); X is selected from nitrogen, oxygen or sulfur,and when X=O, R⁶+R⁷ may represent an alkali earth cation, ammonium ortogether form a heterocyclic moiety;

Particularly preferred organic acids include Structures B through E.

wherein R⁵, R⁶, R⁷ and X remain as defined above for Structure A;

wherein X, R⁵, R⁶ and R⁷ remain as defined above for Structure A andmore preferably X is O;

wherein X, R¹, R², R⁵, R⁶ and R⁷ remain as defined above for Structure Aand more preferably X is O; R¹ and R² are hydrogen;

wherein X, R¹, R⁴, R⁵, R⁶ and R⁷ remain as defined above for Structure Aand more preferably X is O, R¹ and R⁴ are hydrogen;

wherein X, R¹, R⁵, R⁶ and R⁷ are independently defined as above forStructure A and more preferably at least one X is O and at least one R¹is hydrogen; and

wherein X, R⁵, R⁶ and R⁷ are independently defined as above forStructure A and more preferably X is O and R⁵ is hydrogen.

Pamoic acid, or a synthetic equivalent of pamoic acid, is the preferredembodiment. Pamoic acid has a formula corresponding to Structure Fwherein X is O; R⁵, R⁶ and R⁷ are hydrogen.

A synthetic equivalent of pamoic acid is a material that provides thestructural moiety independent of its particular salt, ester, or amideform and that upon pH adjustment yields pamoate functionality suitablefor reaction, optionally with one or two equivalents of anamine-containing active pharmaceutical ingredient to form a pamoatesalt. Examples of synthetic equivalents of pamoic acid capable ofmanipulation to produce pamoate salts include but are not limited to,disodium pamoate, mono-alkali pamoate, di-ammonium pamoate, di-potassiumpamoate, lower molecular weight di-alkyl and/or di-aryl amine pamoate,lower molecular weight di-alkyl and/or di-aryl esters of pamoic acid,and lower molecular weight di-alkylacyl and/or di-arylacyl O-esters ofpamoic acid, i.e. those alkylacyl and arylacyl esters formed using thehydroxyl moiety of pamoic acid and not the carboxylic acid functionalgroup. The descriptor phrase “lower molecular weight” used above meansthe indicated moiety has a molecular mass contribution within thepamoate derivative of less than about 200 amu.

For clarity, the use of lower molecular weight di-alkyl or di-aryl aminepamoate allows for the exchange of higher molecular weight amines, ordrug free bases, to be exchanged for the lower molecular weight aminecomponent during the salt formation reaction. Similarly, the use oflower molecular weight di-alkylacyl and/or di-arylacyl pamoates allowfor their conversion through ester hydrolysis to the pamoic/pamoatemoiety followed by reaction with the desired drug free base.

In a preferred embodiment of the invention, at least one equivalent ofthe amine containing drug substance is reacted per mole of disodiumpamoate to yield the drug substance pamoic acid salt. Preferably, 2:1,1:1, or mixtures thereof, equivalents of amine per mole pamoic acidmoiety or related organic acids are prepared. Typically, an aqueousacidic solution of the amine containing drug substance is combined witha basic solution of pamoic acid or disodium pamoate. The acid/basereaction ensues and the insoluble organic acid salt precipitates fromthe aqueous solution. Optionally, the salt can be purified, dried andmilled to obtain a drug substance ready for formulation into the desireddelivery format. The drug product formulated with the drug substancesthen possesses the targeted delivery characteristics of the drugsubstance and the potential for abuse of either the drug substanceand/or drug product is eliminated or greatly reduced when abuse isattempted via the mucosal surfaces or by injection.

Another feature of the invention is the preparation of pamoate salts forlegitimate active pharmaceutical ingredients wherein the activepharmaceutical ingredient is otherwise used as a synthetic raw materialin the illegal or illicit production of dangerous drugs.

For the purposes of the present invention an API of a drug product isnot directly isolable if it can not be isolated by solubilizing the drugproduct to form a solubilized drug substance and filtering thesolubilized drug substance without further chemical processing.

A useful and unexpected observation was made while preparing theselected organic acid addition salts of these compounds. Bristol et al.(cited above) describes processes for preparing the pamoate, xinafoateand salicylate families of amine-containing controlled substances.Further, and in particular during preparation of the pamoate salts, thesalt precipitated from the reaction mixture and exhibited poorsolubility characteristics in the primarily aqueous reaction medium. Asthe pamoate salts of various controlled substances were isolated, theywere subjected to a host of manipulations to obtain differentpolymorphic forms of the salt. In King et al., also cited above, thesedifferent pamoate polymorphic forms of the same active ingredient weredemonstrated to behave significantly differently than expectation. Ingeneral, the findings reported herein for the opioid active ingredientsdo not follow the observed processing trends or dissolution featuresfound for other organic acid addition salt compounds. The amorphous andpolymorphic forms were shown to have essentially identical dissolutionprofiles. There appears to be a unique feature to the salt formedbetween the opiate moiety and the organic acid components of the presentinvention. Formation of the salt within an aqueous medium affords aprecipitate, however, with unforeseen characteristics. The “solids”formed are very gummy or taffy-like in nature, and exhibit very poorhandling qualities well beyond the normally expected wetcakes isolatedfrom pamoate salt-forming reaction mixtures. The gummy solids provedvery difficult to manipulate for analytical testing or productformulation purposes and careful processing conditions were required toisolate the amorphous and polymorphic forms of the compounds reportedherein.

It is reasoned that the careful isolation conditions are required todefeat the hydrophilic character of the opioids, even as their pamoatesalts, and to remove excess amounts of water from the compounds. Asamorphous and polymorphic opiate salts were isolated, analyticalcharacterization confirmed the presence of water from about 0 to 6percent. Despite this water content, the taffy, or gummy-like nature ofthe original isolates was no longer observed.

Amorphous materials of other, non-opioid, pamoate salts have beenreported in the literature. In U.S. Pat. No. 4,076,942 (Smith et al.)entitled “Crystalline Dipilocarpinium Pamoate”, the inventors describethe amorphous form of this compound as presenting “a drawback in notbeing readily and easily handleable, in being difficult to formulate inan appropriate ocular delivery system and in being difficult to generatestoichiometrically”. The inventors ultimately prepared solvated forms ofthe title compounds which, through a de-solvating process yieldedcrystalline dipilocarpinium pamoate.

The intractable nature of the pamoate salts isolated was a veryunexpected result and required further investigation and assessment at amolecular level. Experiments were conducted to assess the fundamentalcharacteristics of the gums for comparison to other pamoate, xinafoateand salicylate salt families of amine-containing active pharmaceuticalingredients. The differential scanning calorimetry (DSC) thermograms ofthe gums indicated amorphous behavior with low phase transitiontemperatures, generally below 100° C., but with large heats of fusion,generally higher than 100 Joules per gram. Typically for the non-opioidpamoate salts, the amorphous materials had phase transitions greaterthan 100° C. and low heats of fusion, less than 50 Joules per gram.Clearly, the opioid component of the salt was contributing to theparadoxical thermal analysis results.

Without holding to any particular theory or mechanism, it was postulatedthat the abundance of oxygen atom constituents, that is, oxygen atomcontaining substituents or functionality commonly found grouped to oneface/side of the opioid structure may possess sufficient hydrophilicityto entrap or bind water to the molecule. Since the pamoate moiety (orother suitable organic acid component to the salt) would bind to theopioid on the molecule's face containing the nitrogen functionality, theoxygen-atom rich face would be exposed and capable of binding waterthrough strong hydrogen bonding mechanisms. The high heats of fusion andamorphous appearance of the isolated salts along with the poor tactileproperties of the salt support the complexation of water with the salt.These gummy solids were also readily soluble in ethanol, ethyl acetate,tetrahydrofuran and the like, which is a totally unexpectedcharacteristic of pamoate salts. Without additional processing, it isunlikely these salts would have been identified as possessing beneficialanti-abuse properties, e.g. as gummy solids they exhibit ethanolsolubility whereas when isolated as free flowing amorphous orcrystalline powders, ethanol solubility is substantially reduced.

Besides the complexation of water to the salt causing the observedbehaviors, it was unknown if the opioids would exist as both the 1:1 and2:1 (amine:pamoate) salts, or if both were available but onethermodynamically preferred. Two fundamental experiments were conductedto attempt to delineate this possibility. The first was to extend thesalt forming reaction for longer times under higher temperature with theintent to “cure” the salt into a polymorphic form. Further, the reactionconditions were established with the intent of preparing the 2:1 salt.As a control experiment to this approach, the stoichiometry of thereaction was altered to determine if the opioids preferred a 1:1 saltform. Secondly, the preparation of the xinafoate salts were attemptedwhich are by structural restriction limited to yielding only the 1:1(amine:xinafoate) salt. In all cases, gummy, tacky solids were initiallyisolated. Ultimately, the pamoate series exhibited only the 2:1amine:pamoate stoichiometric relationship.

In Bristol et al. pamoate, xinafoate and salicylate families ofamine-containing controlled substances were disclosed which yieldedactive pharmaceutical ingredient salts exhibiting anti-abuse properties.In King et al. it was further demonstrated that these salts may exhibitpolymorphism and in conjunction with the salt's stoichiometriccomposition a dissolution profile could be obtained which providescontrolled release and optionally targeted release of the activeingredient. The fundamental structure of the opioids, which contains themorphine-type ring system and the nearly stereofacial arrangement of anoxygen-rich region of these molecules led to very unexpected findingswith respect to dose dumping. To illustrate this stereofacialarrangement of oxygen atoms, the structure of morphine below representsthis general arrangement within the opiates.

The dose dumping experiments performed were based on a United StatesFood and Drug Administration Guidance developed to evaluate dose dumpingon the opiate, oxymorphone. When applied to the opiate salts of thepresent invention, it was observed that dose dumping could be controlledand prevented at the API level, that is, in an unformulated dosage form.This observation is a unique, unexpected, feature of the opiate saltsreported herein and was confirmed by conducting a set of dissolutionexperiments on imipramine hydrochloride and imipramine pamoate as amixture of amorphous and polymorphic forms. The pH dissolution profilesof these compounds, FIGS. 102 and 104 (hydrochloride and pamoate,respectively), provided results consistent with expectations. However,the dose dumping results were very unexpected: imipramine pamoateexhibited dose dumping properties (FIG. 105) at the three levels ofalcohol content (5, 20 and 40%) tested. Hence, it is reasoned that thepamoate moiety when employed as a salt forming component with an opiatealters the hydrophilic/lipophilic balance of the opiate sufficiently toimpair and compete with hydrogen bonding with the alcoholic solution inacidic media. In contrast, the pamoate salt of imipramine cannotovercome the lipophilic, oily nature of imipramine which is readilysolubilized in an alcoholic, acidic medium. The unexpected behavior indose dumping performance between pamoate salts of imipramine and of theopiates was further confirmation of the herein described technology'seffective application to the opiates. It is acknowledged in the opiateliterature (“Opiates”, by George R. Lenz, Suzanne M. Evans, D. EricWalters, and A. J. Hopfinger, Academic Press, Inc., ©1986, p. 177 andreference cited therein: Med. Res. Rev., 2, 355 (1982), P. R. Andrewsand E. J. Lloyd) that many of the pharmacophores of central nervoussystem (CNS) drugs (including for example imipramine and morphine)possess “rings and nitrogens [which] occupy equivalent spatiallocations”. The authors' assertion is demonstrated by the remarkablesuperposition of the crystal structures of eight diverse CNS drugs.

As is discussed herein, a number of organic acid addition salts of thesefour opioids were prepared and evaluated against dissolution anddose-dumping parameters as compared with the current commercialofferings of these alkaloids as other salt forms. To provide anorganizational framework for the observed discoveries, essentially fivefactors contribute to understanding the invention herein. These are:

1) the hydrophilicity of the opioid;

2) the organic acid family used to prepare the organic acid additionsalt, most preferably a pamoate or xinafoate;

3) the stoichiometry observed from preparation of the organic acidaddition salt;

4) the amorphous versus polymorphic form of the opioid organic acidaddition salt; and

5) the effect of (a) additional organic acid or its conjugate baseformulated with the opioid organic acid addition salt, and/or (b) theeffect of a different organic acid or its conjugate base formulated withthe opioid organic acid addition salt, and/or the effect of thestoichiometric ratio within the formulation between the so namedingredients within (a) and/or (b).

The hydrophilicity of the selected opioids has been discussed videsupra, and it is well known in the industry that careful processing isrequired to remove water from opioids and their salts. Indeed, thepropensity of these opioids to retain water impaired the preparation andisolation of their organic acid addition salts until processes could beidentified which would yield the desired compounds. No doubt, theability of the opioids to retain water impacts their in-vitro andin-vivo dissolution behavior, which to impart an anti-abuse feature tosuch compounds, must be addressed by an alternative mechanism ormechanisms. The following discussion demonstrates how the five factorslisted above were employed to yield a platform technology exhibitingfeatures with the express purpose of curtailing the abuse of themedically important opioids.

FIGS. 1 through 36 and FIGS. 98 through 101 contain the characterizationdata for the organic acid addition salts of the selected opioids.Amorphous and polymorphic forms of each opioid were prepared as theirpamoate salt, and in the case of oxycodone, two pamoate polymorphs wereisolated. For each opioid, the pamoate salt isolated was analyzed as the2:1 (opioid:pamoate moiety) compound. The pamoate polymorphs ofoxycodone did not exhibit inclusion of solvent into the isolatedcrystalline material; however, hydrocodone, hydromorphone and morphinepamoates contained approximately one equivalent of acetone within thecompound. Most interestingly, the acetone adducts, while isolated fromacetone, were not soluble in acetone. Further the compounds (amorphousand/or polymorphic) have poor aqueous and alcohol (iso-propanol)solubility. This solubility property is further elucidated in asubsequent section wherein the anti-dose dumping feature of these saltswas explored in depth as a function of ethanol concentration in acidicmedia. Each of the opioid xinafoate salts was isolated as a crystallinecompound and characterized.

The general (in)solubility features of the cited salts are one aspect ofimparting anti-abuse features to opioid drug substances. The activeingredient, as the free base or a mineral acid salt is often extractedfrom the dosage presentation by employing a readily available organicsolvent such as iso-propanol (IPA), acetone, toluene, xylenes or apetroleum fuel. The poor solubility of the organic acid addition saltsin these media exacerbate the attempts to isolate the active from thedosage form for purposes of abuse.

FIGS. 37 through 97, inclusive, are the graphical representations of thedissolution profiles of the selected opioid salts comparing thecommercial offerings (mineral acid and tartrate salts) with those of thepresent invention. Two types of dissolution profiles are presented: 1)the dissolution profile of the compound as a function of pH, and 2) thedissolution profile of the compound as a function of ethanolconcentration in acidic media which mimics dose dumping. Notsurprisingly, the “traditional” opioid salts currently employed incommerce exhibit pH dissolution and dose dumping profiles substantiatingthe serious abuse potential observed in society. As can be seen in FIGS.37 (oxycodone hydrochloride), 78 (hydrocodone bitartrate), 90(hydromorphone hydrochloride) and 94 (morphine sulfate), each has a pHdissolution profile exhibiting immediate release (IR) characteristics.Indeed, formulation activities by companies offering dosage forms ofthese compounds often yield extended release (ER) dissolutionproperties; yet these measures are quickly defeated by those intent onabusing the active ingredient.

In contrast to the traditional APIs, the dissolution profiles of thecomparable pamoate salts are found in FIG. 38 for amorphous oxycodonepamoate, FIG. 39 for polymorphic oxycodone pamoate, FIG. 96 foroxycodone pamoate in a 2^(nd) polymorphic form, FIG. 49 for amorphoushydrocodone pamoate, FIG. 50 for polymorphic hydrocodone pamoate acetonesolvate, FIG. 52 for amorphous hydromorphone pamoate, FIG. 53 forpolymorphic hydromorphone pamoate acetone solvate, FIG. 55 for amorphousmorphine pamoate and FIG. 56 for polymorphic morphine pamoate acetonesolvate. Several features are notable by comparison of these dissolutionprofiles with those of the traditional salts. First, the pamoate saltsattenuate the immediate release characteristic inherent to the mineralacid/tartrate salts. Indeed, the traditional salts exhibit an immediaterelease profile under all pH conditions. At equivalent concentration ofopioid (i.e. correcting for the molecular weight difference between theopioid pamoate versus its mineral acid salt), the pamoates exhibited anattenuated release profile to the extent an extended release dosagepresentation could be considered wherein this attribute is due to theAPI and not to a formulation technique. Further, it was a highlyunexpected observation counter to pharmaceutical science teaching and tothe invention described in [King, et al.], that there does not appear tobe a difference in dissolution profiles between amorphous andpolymorphic forms of the opioid pamoate salts. In addition, theinclusion of acetone as part of the polymorphic form of the opioidsolvate appeared to have no effect on the dissolution profile ascompared to the non-solvated amorphous forms.

Opioid pamoates are available with or without a solvate. If prepared inDMF and precipitated by addition of isopropanol alcohol the non-solvatedproduct is obtained which can then be formed as an acetone solvate bytaking up in acetone. Oxycodone was not isolated as the acetone solvate.An aqueous solvate is prepared by precipitation in aqueous solution.Without adequate treatment the degree of solvation is difficult todefine. For the purposes of the present invention treatment of aqueousformed salts are treated by vacuum oven to achieve a lower degree ofhydration. For the purposes of the present invention treatment ofaqueous formed salts are subjected to vacuum oven drying to achieve alower degree of hydration. With regards to morphine pamoate vacuumdrying provides a morphine pamoate with less than 3 waters of hydration,whereas dessicant drying at atmospheric pressure provides at least 3waters of hydration.

It is often a concern for the traditional pharmaceutical formulationscientist to formulate with an API which exhibits pH independent releasesuch as that observed for the mineral acid, tartrate and similar salts.Initially, the opioid pamoate dissolution profiles were interpreted tohave the “undesirable” pH dependence yet this characteristic confers anadditional inventive contribution to the present invention. Forinstance, the dissolution profiles are substantially attenuated for thehigher pH conditions and less so for the pH 1 (0.1N HCl) and pH 4.5conditions. This circumstance is not a hindrance to the commercialdevelopment of formulated product offering but represents a desiredfeature. The dissolution at the pH 1 condition is easily manipulated ina proposed dosage by enterically coating the tablet or capsule. Thecoating allows for the tablet to pass from the low pH stomach to thehigher pH intestines where the API is released. Further, the dissolutionprofile for the pH 4.5 condition represents that intermediate rangebetween the low pH of the stomach and the progressively higher pH rangeencountered in the intestines. In all cases, the pamoate exhibits anextended release profile when compared to the traditional salts and theminor pH dependencies are actually advantageous to producing anti-abuseopioid products. For instance, at pH near 4.5, the pamoates would not besoluble in the body's mucosal membranes.

In regard to the opioid xinafoate salts, the comparable dissolutionprofiles are found in the following figures: FIG. 68 for oxycodonexinafoate, FIG. 51 for hydrocodone xinafoate, FIG. 54 for hydromorphonexinafoate and FIG. 57 for morphine xinafoate. The xinafoate moietyrepresents about half of the structural components of the pamoate groupand only the 1:1 opioid:xinafoate moiety salt is available. However, thexinafoate's contribution to the opioid organic acid addition salt isstill quite noticeable in the cited dissolution profiles. Oxycodonexinafoate exhibits a poor dissolution profile at pH 1 with a gradualrelease as the pH increases. This phenomena clearly makes the xinafoatesalt a candidate for an enteric coated, extended release final dosagepresentation. Similarly, hydrocodone xinafoate and morphine xinafoateexhibit similar release properties such that each salt exhibits anextended release at pH 1, and independent release as the pH increases.As with the pamoates, these properties are impediments to attempts tofree base the active ingredient for purposes of abuse. Hydromorphonexinafoate generally exhibits a pH independent release profile and aswith each opioid xinafoate, the release properties are substantiallyattenuated compared with the traditional, commercial salts.

The pH dissolution profiles for opioid pamoates and xinafoates,independent of amorphous or polymorphic considerations, or the inclusionof an organic solvent (e.g. acetone) in the crystalline structure eachrepresent a significant improvement over the traditional mineral acidand/or tartrate salts of these opioids. Further, the pamoates orxinafoates can be directly processed to yield an extended release, pHindependent drug product dissolution profile. Of significant concern washow the additional organic character of these salts would contribute tothe opioids' ability to dose-dump and a more in-depth discussion hereinis warranted.

The US FDA has issued a draft guidance found athttp://www.fda.gov/cder/guidance/bioequivalence/recommendations/Oxymorphone_HCl_ERtab_(—)21610_RC11-07.pdfconcerning oxymorphone hydrochloride and has requested specificdissolution tests be performed to demonstrate alcohol (ethanol) does notpromote dose dumping. A general overview of this concern may be found athttp://www.fda.gov/ohrms/dockets/AC/05/slides/2005-4187S2_(—)02_Hussain.ppt.This Oct. 26, 2005 overview presentation by the deputy director OPS/CDERof the FDA and entitled “Preventing Alcohol Induced Dose Dumping is aDesired Product Design Feature” describes the dose-dumping phenomenon.Dose dumping can be employed by those with the deliberate intention ofabusing the drug, but may also occur during the normal/moderateconsumption of alcohol while taking a prescribed medication. Simply,dose dumping is that condition “in which the complete dose may be morerapidly released from the dosage form than intended, creating apotential safety risk”. Clearly, with the opioid narcotics, dose dumpingfor the intention of experiencing the “high” or rush, may have severe,even deadly consequences. The presentation further categorizes theresults from dose dumping testing as either vulnerable, rugged oruncertain. If the dissolution profile in the presence of alcoholaccelerates the release of the active ingredient, the product isclassified as vulnerable and would likely not receive FDA marketapproval. In contrast, a rugged product design is achieved when thedissolution profile of the drug substance, again in the presence ofalcohol, is identical to or is available to a lesser extent as comparedto the control. The testing regimen recommended within the FDA's draftguidance includes determining the dissolution profile in 0.1N HClsolutions wherein the sample is tested in the medium and at increasinglevels of ethanol, specifically at 5, 20 and 40% alcohol. The currentinvention demonstrates the ability to formulate anti-dose-dumpingpharmaceutical products specifically for those compounds often thesubject of abuse, e.g. oxycodone, hydrocodone, and the like.

The dose dumping phenomenon was evaluated with respect to oxycodonehydrochloride as the standard for comparison since the hydrochloridesalt is most often found in commercial/FDA approved productformulations.

For the initial discussion and to demonstrate the dose dumpingphenomenon, it is useful to consider the following figures: FIG. 58(oxycodone hydrochloride EtOH:water), FIG. 59 (oxycodone hydrochloride),FIG. 79 (hydrocodone bitartrate), and FIG. 91 (hydromorphonehydrochloride). Three dose dumping experiments were conducted onoxycodone hydrochloride. The first experiment employed a modifiedprocedure of the aforementioned standard dose dumping protocol. In thiscase, oxycodone HCl was tested under four conditions: 1) in 0.1N HClcontaining 20% EtOH, 2) in 5% EtOH, 3) 20% EtOH, and in 40% EtOH. Thesubtlety in this experiment demonstrates the dose dumpingcharacteristics in 5, 20 and 40% ethanol and in the absence of theacidic, 0.1N HCl media; the results are graphically represented in FIG.58. The experiment provided an indication of the quantity of oxycodoneextracted by ethanolic solutions and demonstrated a dissolution profileresembling equilibrium solubility was obtained with each of the fourconditions, albeit at different percentages of API released. Equilibriumsolubility is a fixed quantity at a constant temperature and pressurethat is given as the amount of solute contained in the saturatedsolution in a unit amount of the solvent or solution. A maximum amountof oxycodone extraction capability of about 50% could be predicted if apotential abuser used 40% EtOH, (i.e. about 80 proof alcohol). Furtherthe efficiency of the extraction would be highly dependent upon theconcentration of the alcohol employed and if attention was given to thepH of the extraction solution.

In contrast, the experiment was repeated with adherence to the FDA'sdose dumping protocol wherein, a volume of the 0.1N HCl dissolutionmedia was progressively replaced with 5, 20 and 40% concentrations ofEtOH. The results of this experiment are captured in FIG. 59. Here too,dissolution profiles resembling equilibrium solubility were obtainedquickly, i.e. apparent solution equilibrium was obtained within minutes.Not surprisingly, the control condition using 0.1 N HCl without EtOHexhibited complete dissolution within minutes. By contrast, theprogressive replacement of the dissolution media with the specifiedincreasing amounts of EtOH led to diminished API release. Clearly, thepresence of the acidic media, independent of the ethanol concentrationenhances the release profile of oxycodone hydrochloride by more than 20%(absolute) at each ethanol level as can be seen by comparing FIGS. 58and 59. However, the test condition absent EtOH provided the highestconcentration of the opiate in a very short time. As an aside, currentcommercial forms of oxycodone HCl, such as Oxycontin®, employ anextended release formulation technique to prevent the immediate releaseof the API which can have serious and highly detrimental health effectsto a patient. Hence, the time dependent, extended release property ofthe drug is deliberately defeated by individuals intent on abusing thedrug by using alcohol to release the API from its formulated matrixwhile in the presence of stomach acid; immediate release is predictableand with the associated consequences. An inspection of FIGS. 79 and 91indicate hydrocodone bitartrate and hydromorphone hydrochloride,respectively, exhibit dose dumping propensities. It should become clearthat formulation mechanisms relying on differential solubilities of thetraditional API salts as a function of pH and solvent concentration toyield a drug product presentation exhibiting 1) pH independent extendedrelease when used in the body and 2) impart anti-dose dumping properties(whether for intended abuse or just to a non-compliant patient) is anearly impossible task when employing traditional API salts.

In contrast, the organic acid addition salts of the present inventionoffer another alternative. The dose dumping characteristic wasinvestigated for the opioid pamoate and xinafoate salts and summarizedin the following figures: FIG. 63 for amorphous oxycodone pamoate, FIG.65 for polymorphic oxycodone pamoate, FIG. 67 for oxycodone xinafoate,FIG. 49 for amorphous hydrocodone pamoate, FIG. 50 for polymorphichydrocodone pamoate, FIG. 87 for amorphous hydrocodone pamoate acetonesolvate, FIG. 88 for polymorphic hydrocodone pamoate acetone solvate,FIG. 82 for hydrocodone xinafoate, FIG. 92 for amorphous hydromorphonepamoate, FIG. 93 for polymorphic hydromorphone pamoate acetone solvate,and FIG. 95 for polymorphic morphine pamoate acetone solvate. In eachcase, the dose dumping response was dramatically improved as compared tothe comparable API as its mineral acid or tartrate salt. Surprisingly,the unexpected result was the increased organic nature of the opioidpamoate or xinafoate salts did not increase the solubility of thematerial in acidic media containing increased amounts of ethanol (i.e.5-40% ethanol).

A similar set of experiments was conducted on oxycodone pamoate withadditional dose dumping dissolution profiles obtained to distinguishbetween the amorphous and polymorphic forms of oxycodone pamoate. Tofirst address the amorphous oxycodone pamoate dose dumping experiments,the results obtained from the modified dose dumping protocol (analogousto the method used for obtaining those results in FIG. 58) aresummarized in FIG. 61. It should be noted that the HPLC analyses of theorganic acid addition salts of the present invention exhibit detectionpeaks for both the free-base opioid and for the particular organic acidfamily employed (pamoate and/or xinafoate and their derivatives). FIG.62 corresponds to FIG. 63 except that the pamoate concentration wasplotted as a function of time instead of the release of the opiate. Anumber of observations were made from these FIGS. 62 and 63. First, theopiate when delivered as the pamoate salt to the 0.1N HCl media does notexhibit an immediate release profile; release is complete at timesapproaching one hour. Certainly, this release profile is not what issought by one attempting to abuse the drug. When 40% EtOH is employed toenhance dose dumping, the amount of opiate released was time dependentbut reaches an apparent equilibrium solubility concentration greaterthan the same condition observed for oxycodone HCl in 40% EtOH. Thisincrease from about 50% opiate immediately released for thehydrochloride salt versus the approximately 60% released opiate overabout one hour when delivered as the pamoate represents a significantdecrease to dose dumping potential. Additionally, it required aboutninety minutes before appreciable amounts of the opiate were releasedfrom the pamoate under the 5 and 20% EtOH conditions. As such, dosedumping would not be a preferred route of abuse administration ifoxycodone pamoate was employed in a formulated product. This conclusionwas further supported by the results summarized in FIG. 62 particularlywhen the pamoate concentration was determined for the 40% ethanolcondition. The time dependent release of the pamoate moiety, in FIG. 62,was observed and corresponded well to the release of the opiate in FIG.61 for 40% EtOH. The apparent pamoate equilibrium solubility wasachieved after approximately 45 minutes, to yield about 85% of thepamoate released. A superficial analysis of these data may lead one toconclude the opiate could be effectively extracted from a dissolutionmedia of 80 proof alcohol and to easily separate the pamoate moiety formthe oxycodone. However, the opiate and the pamoate are present in thedissolution medium and removal of the solvent by evaporation will onlylead to the reformation and precipitation of oxycodone pamoate.Consequently, there is no benefit by a potential abuser to attempt dosedumping with 40% ethanol. In addition, by inspection of either FIG. 61or 62, dose dumping at 5 and 20% is a slow linear process.

These experiments were repeated using the FDA's dose dumping protocolwherein present in the various ethanol concentrations was 0.1N HCl.Results from these experiments are summarized in FIG. 63. The amorphousoxycodone pamoate exhibits a modified release profile in 0.1N HCl withfull release occurring after about one hour. The presence of alcoholsignificantly impacts the release of the opiate and in this case withacid present, no dose dumping benefit would be obtained by a drug abuserby drinking a bottle of 80 proof alcohol to accelerate release of theopiate. In fact, drinking beer (nominally 5% EtOH) would diminishrelease of the opiate. Further FIG. 65 summarizes the results from thedose dumping experiment conducted on a polymorphic form of oxycodonepamoate. The polymorphic form which had exhibited an essentiallyidentical pH dissolution profile as the amorphous form, exhibited anunexpected and modified release profile under the FDA's dose dumpingprotocol. The dissolution profiles for the 0.1 N HCl and that containing5% EtOH exhibited an extended release profile wherein about 70% of theactive was released in approximately sixty minutes. Overall, thedissolution profiles for these two conditions were quite similar. Incontrast, the 20% EtOH profile reached approximately a 10% equilibriumsolubility in about 30 minutes. The 40% EtOH condition exhibited adelayed release profile with approximately a 10% release after about 80minutes with a gradual rise to approximately 40% release after 3 hours.These results indicate essentially no dose dumping effects, orextraction capabilities are available to the oxycodone pamoates presentas either the amorphous, polymorphic or combinations of both forms. Likethe pH dependent dissolution profiles for oxycodone pamoate (FIG. 38)amorphous and FIG. 39 (polymorphic), the dose dumping profiles for theamorphous polymorphic pair did not significantly distinguish betweenthese forms of the drug substance yet both attenuated dose dumping ascompared to oxycodone hydrochloride.

While much of the attention herein has been placed on oxycodone pamoateas a means to elucidate and identify the extended release and anti-dosedumping mechanisms, the findings are applicable to the family of opioidcompounds. The pamoate salts appear to be the most generally applicable;however experiments with the xinafoate salts have also proved fruitful.The xinafoate salts of oxycodone, hydrocodone, hydromorphone andmorphine each demonstrated some level of extended release property atvarious pH values and could accommodate formulations designed to obtaina pH independent release. These properties are easily observed aspresented in FIG. 54 (hydromorphone xinafoate) as compared with FIG. 90(hydromorphone hydrochloride). Clearly however, the xinafoate salts donot have the dominating role in interrupting dose dumping as well as thepamoates perform. For instance, comparing FIG. 63 (amorphous oxycodonepamoate) vs. FIG. 67 (oxycodone xinafoate); the xinafoate salt dosedumps immediately at the higher EtOH concentrations. Interestinglyhowever, the xinafoate salt has a significantly attenuated dose dumpingprofile when compared with the comparable hydrochloride salt.

Many, many comparisons such as these are possible from the extensivedata set, which may overshadow some fundamental conclusions:

1) the hydrochloride and bitartrate salts exhibit immediate releaseprofile and are highly susceptible to dose dumping;

2) the pamoate and xinafoate salts attenuate the pH dissolution profilesof the opioids and impart a level of extended release directly to theactive substance;

3) the pamoate and xinafoate salts are suitable for providing pHindependent release drug product formulations;

4) the expected differences between the amorphous and polymorphic opioidpamoate salts were essentially non-existent and consequently contrary toaccepted pharmaceutical teachings;

5) the solvated forms of the amorphous and/or polymorphic forms of theopioid pamoate salts had little impact on their dissolution profiles ordose dumping properties; and

6) the pamoate salts are a dominating factor in preventing dose dumpingand are independent of the opioid.

Analogous to the traditional dissolution tests discussed herein,formulation experiments were conducted to determine the effect of anexcess stoichiometric amount of the pamoate and/or xinafoate moiety onboth the pH dependent dissolution tests and dose dumping protocol.Experiments were conducted with disodium pamoate (dispam), pamoic acidand 3-hydroxy-2-naphthoic acid (BON Acid) in various ratios expressed asa molar ratio between the particular opioid salt evaluated (e.g.oxycodone pamoate) and the additional organic acid component (perhaps asits alkali metal salt). Control experiments were performed on the simplehydrochloride, sulfate and bitartrate opioid salts as a basis forcomparison to the opioid pamoate and xinafoate salts when formulatedwith additional organic acid component.

This investigation generated a large data set with striking conclusions.The addition of excess amounts of the pamoate or xinafoate moieties toan opioid pamoate or xinafoate salt, i.e. a formulation, providedmarkedly attenuated pH dissolution profiles and significantly inhibiteddose dumping. A review of the oxycodone series of experimentsillustrates this conclusion well and was demonstrated to be applicableto the family of opioids in general. The stoichiometry rangeinvestigated for dispam was 2:1 to 1:2 opioid salt to dispam andincluded the 1:1 mid-range condition. Screening experiments indicatedthe desired effects were less pronounced when employing BON Acid orpamoic acid, however, specific experiments were conducted at similarstoichiometric ratios as those performed employing dispam and includedthe “cross” experiments. The “cross” experiments include thoseconditions wherein more than one organic acid component was added andwherein the additional organic acid component was different from thecounter-ion employed to produce the opioid salt.

Pertinent to the discussion regarding formulation experiments and by wayof example regarding the nomenclature identifying each experiment,consider FIG. 40 (oxycodone hydrochloride 2:1 dispam). The parentheticaldescriptor indicates the API was oxycodone hydrochloride which wasformulated in a 2:1 stoichiometric ratio with disodium pamoate.Similarly, FIG. 44 (oxycodone hydrochloride 1:1:1 dispam:pamoic)indicates oxycodone was formulated in a 1:1:1 ratio with dispam andpamoic acid. For completeness and in context of the present invention,another example of the nomenclature employed is represented by FIG. 77(oxycodone pamoate polymorph 1:2 BON Acid) symbolizing the evaluation ofa polymorphic form of oxycodone pamoate was formulated with astoichiometric excess of BON Acid in a ratio of 1 mole of the API and 2moles of BON Acid.

The following figures represent the control experiments related tooxycodone hydrochloride for pH and dose dumping dissolution profiles:FIG. 40 (oxycodone hydrochloride 2:1 dispam), FIG. 41 (oxycodonehydrochloride 1:2 dispam), FIG. 42 (oxycodone hydrochloride 2:1 pamoicacid), FIG. 44 (oxycodone hydrochloride 1:1:1 dispam:pamoic acid), FIG.42 (oxycodone hydrochloride 2:1 pamoic acid), FIG. 45 (oxycodone base2:1 pamoic acid), FIG. 70 (oxycodone hydrochloride 1:1 dispam), FIG. 60(oxycodone hydrochloride 1:1 dispam), FIG. 69 (oxycodone 2:1 dispam),FIG. 71 (oxycodone hydrochloride 1:2 dispam) and FIG. 72 (oxycodonehydrochloride 1:2 pamoic acid).

Several valuable conclusions can be drawn from the oxycodonehydrochloride formulation series when compared with the APIhydrochloride alone. The comparison between the pH dissolution profileresults contained in FIG. 37 (oxycodone hydrochloride) compared thecomparable formulation experiment summarized in FIG. 70 (oxycodonehydrochloride 1:1 dispam) is most instructive. FIG. 37 illustrates theimmediate release nature of the hydrochloride salt; FIG. 70 demonstratesthe ability to provide an extended release profile independent of pHexcept for the pH 4.5 condition as an outlier. The pH 4.5 condition isrepresentative of a desirable design feature of the invention such thatthe combination of oxycodone hydrochloride and dispam provides amaterial exhibiting limited solubility in the pH range associated withthe physiological pH of the mucosal membranes. Consequently, formulationof the active ingredient with dispam incorporates one line of defensetoward the abuse of the drug. It is well noted that the physicaladmixture of the solid active ingredient hydrochloride with soliddisodium pamoate did not produce any sign of salt formation as evidencedby analytical methods (FTIR, PXRD, DSC). The dose dumping criteriainvestigated as well as the results are summarized in FIG. 60 (oxycodonehydrochloride 1:1 dispam) and can be compared with the controlexperiment, FIG. 59 (oxycodone hydrochloride). For oxycodonehydrochloride alone, equilibrium concentrations are reached reasonablyquickly and are an indication that the active would be susceptible toextraction by alcohol. Conversely, the formulation of the active opiatewith dispam shuts down its propensity to dose dump with only smallamounts of active available after more than an hour. Clearly, anindividual intent on abusing a drug formulated with dispam would not bewilling to wait up to ninety (90) minutes for only about half the drugto become available while employing alcohol to accelerate the release ofthe drug. Lastly, for oxycodone hydrochloride, FIG. 69 (oxycodonehydrochloride 2:1 dispam) and FIG. 72 (oxycodone hydrochloride 1:2pamoic acid) demonstrate other aspects of the invention. The combinationof 2:1 active to dispam indicates that level of dispam is insufficientto totally quell dose dumping, while the use of pamoic acid provides atight spread in the dose dumping response; it too would not be the bestchoice for inhibiting dose dumping. Consequently a preferred embodimentof the invention constitutes the admixture of oxycodone hydrochloride ina 1:1 molar ratio with dispam.

Continuing with the oxycodone series with respect to formulation,oxycodone pamoate provides a further refinement of the invention. Forthe amorphous series of oxycodone pamoate, the following paired figures(pH and dose dumping dissolution profiles respectively) are useful toconsider: FIG. 46 (oxycodone pamoate 1:1 dispam) and FIG. 64 (oxycodonepamoate 1:1 dispam, and FIG. 38 (oxycodone pamoate) and FIG. 63(oxycodone pamoate). The analysis of FIG. 73 (oxycodone pamoate 1:2dispam) and FIG. 74 (oxycodone pamoate 1:2 BON Acid) also contributes tothe following conclusions:

1) oxycodone pamoate (amorphous or polymorphic) exhibits an extendedrelease pH dissolution profile and significantly reduces dose dumping;

2) formulation of oxycodone pamoate with dispam further imparts ananti-abuse feature and restricts dose dumping;

3) additional dispam (2 molar equivalents) does not provide additionalquelling of the dose dumping phenomenon; and

4) the addition of BON Acid demonstrated its ability to decrease dosedumping.

The oxycodone pamoate polymorphic series supported these conclusions aswell as seen in the paired figures (pH and dose dumping dissolutionprofiles respectively), FIG. 48 (oxycodone pamoate polymorph 1:1 dispam)and FIG. 66 (oxycodone pamoate polymorph 1:1 dispam). This pair offigures, FIGS. 48 and 66 represent an excellent embodiment of theinvention to ultimately yield an extended release product that is notsusceptible to dose dumping.

The results in FIG. 75 (oxycodone pamoate polymorph 1:2 dispam)represents a unique opportunity arising from these specialized organicacid addition salts formulated with additional acid component fortargeted release directly to the bowel. The mixture exhibits a slowrelease of active opiate at both pH 1 and pH 4.5 but a faster release atthe higher pH. The presence of dispam also inhibits dose dumping (in thestomach by consumption of alcohol).

In order to ascertain the depth and breadth of the discoveriesassociated with oxycodone, a similar approach based on a truncatedseries of experiments was implemented to investigate the response andreceptiveness of other opioid salts to formulation techniques. A fewexemplars are noteworthy. For the control experiments regardinghydrocodone bitartrate, the following paired figures (pH and dosedumping dissolution profiles respectively) should be considered: FIGS.80 and 81 (hydrocodone bitartrate 1:2 BON Acid). The addition of BONAcid to the formulation has a significant effect, particularly atattenuating the pH dissolution profile. However, while BON Acid impactsthe dose dumping propensity of the bitartrate, it is not completelyadequate at eliminating this phenomenon. Conversely, when BON Acid wasemployed with hydrocodone xinafoate, excellent results were obtained.The analysis of the paired figures (pH and dose dumping dissolutionprofiles respectively) for FIG. 83 and FIG. 84 (hydrocodone xinafoate1:2 BON Acid) indicate, first, a pH independent response is obtained forthe pH dissolution profile with the exception of the pH 1 conditionwhich can be addressed by an enteric coating. In other cases it ispreferable to not have an enteric coating. Further, the formulation doesnot does dump since equilibrium solubility is reached quickly at the 40%ethanol condition while only low levels of active ingredient isavailable at the more reasonable ethanol concentrations.

From these formulation exercises clear conclusions can be reached:

1) the addition of dispam to either the mineral acid or bitartrateopioid salt assists in converting the traditional API release profile toan extended release profile exhibiting some tendency toward a pHindependent release except at pH 1;

2) the addition of dispam to opioid organic acid addition salts (e.g.morphine pamoate, hydromorphone xinafoate and the like), creates asynergistic effect greater than the effect seen when mineral acid opioidsalts are employed for both the pH and dose dumping dissolutionprofiles;3) “cross” salt experiments, e.g. oxycodone pamoate formulated with BONAcid, provide improved performance properties;4) the preferred selection order of organic acid component additions forproviding anti-abuse properties, including but not limited to extendedrelease dissolution profiles and the prevention of dose dumping is:dispam>BON Acid>pamoic acid;5) the preferred selection order for the addition of excess dispam molarequivalents for imparting anti-abuse properties, including but notlimited extended release dissolution profiles and the prevention of dosedumping (API:dispam) is: 1:1>1:2>2:1;

The performance features enabled by the present invention are notlimited to the anti-abuse properties imparted by the organic acidaddition salts, but also include advances to the manufacture of finishedpharmaceutical product dosage presentations. The salts disclosed herein,and the ability to influence their dissolution behavior by formulationvia the addition of the organic acid component extends as well toexisting drug product formulations exhibiting extended release,controlled release and anti-abuse properties. Indeed, the presentinvention is compatible with existing drug product formulations whichprovide extended/controlled release, pH independent release of theactive ingredient, and/or anti-dose dumping features and furthercontributes to the success of these earlier technologies by: 1) reducingthe potential variability observed in unit dose manufacturing, and 2)improving the robustness of the manufacturing process.

The hygroscopic nature of the opioids is well known, and as theirmineral acid or small organic acid salts, these materials exhibit highsolubility in water or organic solvents, especially ethanol. This verysolubility hinders formulated dose manufacturing since processesemployed to impart anti-abuse features such as wet granulation orparticle coating may lead to the opioid salt dissolving instead ofagglomerating or being receptive to coating. Consequently, the purposeof the formulation to impart anti-abuse properties (inhibit extractionof the active from dosage form), requires difficult manufacturingprocedures using materials essentially incompatible with themanufacturing process required. Of the many consequences to thismismatch of purpose and manufacturing capability is the likelihood ofdose uniformity failure, i.e. too much tablet-to-tablet, orcapsule-to-capsule dose variation.

In contrast, the opioid salts of the present invention and theirformulations disclosed herein improve the capability of commerciallyexisting opioid formulations and provide more manufacturing options forformulation techniques. By way of example, the higher molecular weightsof the salts disclosed herein allow for more accurate weighing,dispensing and formulation of the opioid active as compared with themineral acid salts. Oxycodone hydrochloride has a molecular weight ofabout 352 grams/mole whereas the pamoate salt has a molecular weightmore than two and one-half times larger. To obtain dose uniformity onhighly active compounds, such as the opioids, it is much easier to weighthe larger mass required for equal dosing when using the pamoate saltthan it is for the hydrochloride salt, or similar low molecular weightsalt. As the physiological activity of the opioid increases, thisbenefit attributable to the molecular weight difference increasesdramatically. To a patient who obtains an incorrect dosageadministration, the medical consequences can be severe; too low and atherapeutic dosage is not obtained; too high and death may occur. Inaddition to the molecular weight differences, pre-formulation of theopioid organic acid addition salt with additional organic acid component(same or different to that forming the salt, i.e. cross salts), allowsfor greater dosage control in the fully formulated drug product. Indeed,this pre-formulated material is suitable for use as the formulatedproduct—in a tablet by direct compression or in a capsule.

The manufacture of a formulated drug product optionally includes, but isnot limited to the following steps:

a) wet or dry granulation;

b) direct compression tablet pressing

c) particle coating followed by drying;

d) sieving and/or sizing

e) milling;

f) blending with additional excipients;

g) optionally, additional wet or dry granulation;

h) optionally, sizing and milling

i) blending with additional excipients;

j) tablet pressing or capsule filling;

k) pan or tumbler coating and drying; and

l) packaging.

The traditional opioid salts do not lend themselves well to processingsteps requiring wet granulation or particle coating. For instance,opioid salt particle coating employing a fluid bed coater with a liquidspray containing a performance based or functional polymer dissolved ina solvent (typically water or alcohol) with the intention of coating theopioid particle is very difficult. As described, the intention of thepolymer coating on the opioid mineral acid salt, or the like, is toprepare a matrix which imparts an anti-abuse property to the otherwisereadily available salt. Under the processing conditions described, thetraditional opioid salt is prone to dissolve and yield non-uniformagglomerates at best. It is impractical therefore to attempt particlecoating as a general procedure to apply anti-abuse coatings to theopioid salt. However, the salts disclosed in the present invention arequite amenable to these coating processes, as well as to wet or drygranulation techniques. Additionally, drug product produced using theorganic acid addition salts and cross-salt formulations described hereinprovide an immediate track and trace capability to prevent diversion,[King, et al.].

An important benefit and comparison enabled herein is the in vitro/invivo correlation of the existing opioid-based drug products (e.g.Oxycontin® marketed by Purdue Pharmaceutical) with the inventiondisclosed herein. For instance, U.S. Pat. No. 5,508,042 [Oshlack et al.]discloses a controlled release oxycodone composition and claims rangesof blood plasma concentration as a function of time. The extendedrelease property was achieved singularly through formulation techniquesto overcome the widely known release property of oxycodone hydrochloride(as provided herein for reference; see FIG. 37), and indeed theexperimental enablement section of the '042 patent uniquely usesoxycodone hydrochloride as the source of active ingredient.Commercially, the extended release feature has been insufficient todefeat attempts at abuse and the formulation is not resistant to dosedumping. Similarly, and not surprisingly, Purdue pulled Palladone®, anextended release capsule product, from the market in 2005 because theactive ingredient, hydromorphone hydrochloride, exhibited dose dumping.Clearly, there has remained an on-going need in society and in themarketplace to provide the medical benefits achievable through the useof opioid products. Indeed, their use is considered a medical necessityfor relieving pain. However, intentional or unintentional abuse of theseproducts via dose dumping can be eliminated by implementation, in wholeor part, of the invention herein. Consequently, the invention provides ameans to achieve therapeutic levels of medically prescribed opioid whilepreventing abuse, including dose dumping. In other words, the inventionprovides a means for reducing the range in daily dosages required tocontrol pain in human patients, comprising administering an oralcontrolled release dosage formulation comprising from about 10 to 40 mgoxycodone or a salt thereof which provides a mean maximum plasmaconcentration of oxycodone from about 6 to about 60 ng/mL from a mean ofabout 2 to about 4.5 hours after administration and a mean minimumplasma concentration from about 3 to about 30 ng/mL from a mean of about10 to about 14 hours after repeated administration every 12 hoursthrough steady-state conditions, said concentrations and mean timesunaffected by the presence of alcohol imbibed by the patient. Theinvention also allows for reducing the range in daily dosages requiredto control pain in substantially all human patients comprisingadministering an oral solid controlled release dosage formulationcomprising from about 10 mg to about 160 mg oxycodone or a salt thereofwhich provides a mean maximum plasma concentration of oxycodone up toabout 240 ng/mL from a mean of up to about 2 to about 4.5 hours afteradministration and a mean minimum plasma concentration up to about 120ng/mL from a mean of about 10 to about 14 hours after repeatedadministration every 12 hours through steady-state conditions, saidconcentrations and mean times unaffected by the presence of alcoholimbibed by the patient. Further, the invention disclosed herein allowsfor the therapeutic administration of an opioid at allowable minimum andmaximum plasma concentrations sufficient for the relief of pain asextended release formulations dosed at about 12 hour intervals tomaintain blood plasma concentrations within the minimum and maximumtherapeutic range, said minimum and maximum blood concentrationsunaffected by the presence of alcohol imbibed intentionally or otherwiseby the patient receiving the therapeutic administration of the opioid.

The present invention is applicable to a variety of drug deliverypresentations including solid oral dose, parenteral dosage forms(depo-type products) and by devices and formulations suitable fortransdermal delivery and nasal/inhalation administration. It isresponsibly acknowledged that many factors may influence the overallpharmacokinetic profile of a drug product, for instance, the particlesize distribution of the drug substance may markedly influence drugsubstance bioavailability. Hence, the optimum practice of this inventionwhen employed for a specific drug product must account for the multitudeof additional factors. The benefit of the current invention is a meansto provide a dominating or controlling factor to prevent abuse whileachieving efficacious and therapeutic patient dosages to whichrefinements, adjustments or modifications can be asserted to yield anoptimal response.

The three primary mechanistic approaches to prohibiting abuse;antagonist, prodrug and formulation; attempt to address abuse potentialby impacting the route of administration, or to differentiate thephysiological environment in which the drug fulfills its intendedpurpose versus the drug's misuse. Each of these routes was shown topossess inherent limitations for mitigating drug abuse. For the purposesof additional clarity and completeness, the mineral acid salts, whichare typically abused, do not exhibit a suitable means to prevent abuse.The dissolution properties of the mineral acid salts of thephysiologically active and/or controlled substance amines consistentlyexhibit high dissolution rates and substantial achievable release rates(85-100%) over the entire physiological pH range.

In contrast, it is relevant to the present invention to note theimportance of pH in controlling the release of a drug substance from itsproduct formulation to achieve absorption and consequently, themedicinal effect. The pH of the gastrointestinal tract essentiallyremains highly acidic with the exception of the lower colon whichreaches pH 8; vaginal pH is typically around 5.8 and the nasal cavity isapproximately pH 4.5. More generally, each of the mucosal surfaces,particularly ocular, nasal, pulmonary, buccal, sublingual, gingival,rectal and vaginal are receptive to drug absorption if release canoccur. A dominating feature of the present invention is the severelyretarded release of the controlled substance, particularlyamine-containing pamoate salt (or related salt family) in the pH rangeof about 4 to 9 which encompasses the physiological pH of the mucosa.These release properties were an unexpected finding recognized andobserved after performing dissolution tests over a wide pH range onseveral unrelated compounds. The release properties and saturationsolubility profiles are a means to evaluate a reasonable dosageapplication to the mucosa. The non-release of the drug in the 4 to 9 pHrange negates absorption and prevents the physical act of abuse. For theamine-containing hydrochloride salts, an abuse mechanism remainsoperative since these salts do not exhibit the discriminating “on/off”switch of the present invention.

An experimental refinement of the dissolution tests was performed onseveral compounds to better represent the physiological conditionsencountered during abuse attempts and to account for the saturationsolubility factor. Further, control experiments were included in theexperimental design to compare the organic acid addition salts of thecurrent invention with the hydrochloride salts of identicalamine-containing controlled substances. In some cases, model compoundswere used to demonstrate the principles of the invention instead ofusing compounds legally designated as controlled substances.Side-by-side dissolution experiments on hydrochloride salts versus thoseof the present invention were conducted at three different pHconditions: a) a pH of about 1 to simulate gastric conditions, b) pH ofabout 4.5 to simulate mucosal surface pH, and c) a pH of about 7 toevaluate a potential pH range of mucosal surfaces and blood pH forpurposes of simulating injection. In addition, the experimentation wasdesigned to demonstrate the equivalence of the organic acid additionsalts to the mineral acid salts if used by their intended route of oraladministration route and hence the concentration effects were includedin the study. For oral administration of a dosage form, the UnitedStates Pharmacopeia (USP) recommends the immediate release testingprocedure on a unit dosage to be performed on a simulated stomach“solution” volume of 900 mL. For the mucosal membranes, the availablemucous fluid may be better approximated at 10 mL. Hence, dissolutiontests were conducted at different concentrations at the different pHlevels. Besides temperature, pH and concentration, the time factor wasalso evaluated under the presumption that an individual abusing a drugwill want to obtain their anticipated physiological response within anhour.

Also disclosed herein are processes for the preparation of drugsubstances and DEA controlled drug substances (APIs) using organic acidaddition salts of the active pharmaceutical ingredient (API) which areoptionally formulated with other non-therapeutic materials to aid indelivery, stability, efficacy, targeted release and to engineer apharmacokinetic profile of the organic acid addition salts as comparedto other salt forms, including inorganic (mineral) acid salt forms. Thepresent invention provides for release of the API for its intendedpurpose and prevents availability of the drug substance for typicalroutes of abuse. The present invention describes a method forevaluating, and formulations for, the organic acid addition salts ofappropriate APIs to provide an efficacious and therapeutic dosage toanimals and humans.

A drug formulation which is selected for the prevention of drug abuse isspecifically a drug which is bio-unavailable or not isolable if effortsto alter the intended or established route of administration areundertaken. In a preferred embodiment the drug formulation is notreleased under aqueous conditions at a pH of about 4 to about 9 andgenerates a solid of an organic acid at pH below about 4. At pH aboveabout 9, the organic acid (as its inorganic salt) and the aminecontaining active pharmaceutical ingredient (as its free base) aresufficiently soluble as to prevent separation of the components and thusinhibiting direct isolation of the API (as its free base) withoutadditional processing.

In the present invention a drug product can be prescribed andadministered in a manner wherein proper administration provides atherapeutic effect and the function of the API is realized. With adifferent manner of administration, in other words, a non-therapeuticadministration of the API does not enter the bloodstream in an amountsufficient to be active. To be effective the API must be bio-available.For the purposes of the present invention, one method of establishing acompound's bio-availability is by determining the percentage of weightAPI recovered from an aqueous solution at a pH representative of themethod of administration described herein. For the purposes of thepresent invention a compound is considered to be effective when lessthan 85 wt % of the compound is recovered from an aqueous solution at apH representative of the method of administration. If, by contrast forexample, 85 weight percent or more of a drug compound is recovered froma solution at a pH of 4-9, pH 7 for example, the material is consideredto be bio-unavailable at a mucosal membrane and is considerednon-permeable at the mucosal membrane and the compound exhibitsprophylactic properties. If, for example, less than 85 weight percent ofa drug compound is recovered from a solution at a pH of less than 4, pH1 for example, the material is considered to be bio-available under oraladministration and is considered permeable in, for example, thegastrointestinal tract due to the release of the API at the pH of thegastrointestinal tract. For the purposes of the present inventiontherapeutic dose is characterized as immediate dose, slow dose andcontrolled dose. An immediate dose is defined as a formulation whereinat least 85 wt % of the active ingredient is bioavailable at 1 hour at arepresentative pH. For example, 1 N HCl. For the purposes of the presentinvention bioavailable is defined as the weight percent which is notrecovered by filtration. Slow release is defined as a formulationwherein at least 50 wt % to less than 85 wt % of the active ingredientis bioavailable at 1 hour at a representative pH. Controlled release isdefined as a formulation wherein no more than 50 wt % of the activeingredient is bioavailable at 1 hour at a representative pH. Morepreferably, with controlled release at least 12.5 wt % to no more than42.5 wt % is bioavailable at 1 hour at a representative pH. In oneembodiment the representative pH approximates the stomach pH whichcorresponds to 0.1 N HCl. It is particularly preferred that therepresentative pH be between 1.6 and 7.2.

A particularly preferred embodiment and method of administering theamine-containing pharmaceutically active compound is by oral dose. Theoral dose is prepared by first preparing an organic acid salt of theactive compound. The organic salt is then formulated into a carriermatrix to provide an oral dose drug product. The carrier matrix iscomposed of ingredients (excipients) optionally selected from the group,but not limited to binders, fillers, flow enhancers, surfactants,disintegrants, buffers, and the like, typically employed in the art andfound in the “Handbook of Pharmaceutical Excipients”, Rowe, Sheskey andOwen (Editors), Fifth Edition, 2006, Pharmaceutical Press (publishers).When the oral dose is ingested the organic salt dissociates underphysiological conditions. The organic acid portion of theamine-containing organic acid addition salt forms the insoluble(organic) acid while the active compound is liberated and becomesbio-available. Efforts to directly isolate the active compound from theoral dose would be thwarted as described herein.

An “alkaloid” is an amine nitrogen containing natural product, orsynthetically modified or derivatized natural product, or whollysynthesized analog of a natural product, or an amine containing compoundthat exhibits biological activity in animals or humans. The aminenitrogen can be present as a primary, secondary, tertiary or quaternaryamine moiety and a given compound may contain more than one type ofamine functionality. Examples of these materials are the US DrugEnforcement Agency's (DEA) Form 225 of Schedule I through V controlledsubstances, generally divided between narcotic and non-narcoticmaterials. There are also other compounds applicable to the presentinvention not found on the DEA list or which may be added to it in thefuture. Further, the compounds applicable to the present invention mayarise from plant or animal origin, or may be totally obtained throughhuman effort of design and synthesis. A reference to compound classes(pharmocophores) applicable to the invention are found within Strategiesfor Organic Drug Synthesis, by Daniel Lednicer, published by John Wileyand Sons, Inc. © 1998, Chapters 7 through 13 inclusive and individually,Chapter's 13 and 15. Classes of compounds subject to this inventioninclude but are not limited to opiates, morphinoids, tropinoids,amphetamines, compounds containing a piperidine or substitutedpiperidine sub-structure within the molecule, benzodiazepines,benzazepines, and compounds containing a phenethyl amine or substitutedphenethylamine sub-structure within the molecule. The commoncharacteristic to each compound is the presence of an amine nitrogenwhereby the amine nitrogen is either a primary, secondary or tertiaryamine group and is capable of forming a salt with an inorganic ororganic acid, or combinations thereof. Within the description of theinvention, the term alkaloid or amine may be used interchangeably toidentify a compound possessing, or suspected of possessing, biologicalactivity in humans or animals, in its free base (non-salt form) or in asalt form. The differentiating factor defining the invention is thealkaloid's ability to form an organic acid salt that will retain theexpected biological activity when used as intended for legitimatetherapeutic purposes, but is not readily accessible for abuse byinhalation (smoking), mucosal application, nasal absorption (snorting)or by intravenous injection (shooting).

A “drug substance” is a molecular entity or compound, also known as anactive pharmaceutical ingredient (API) that exhibits biological activityfor the purpose of providing human or animal medication to treatdisease, pain or any medically diagnosed condition. It is possible for adrug substance to be used in combination with one or more different drugsubstances to ultimately impart a biological response in humans oranimals. A drug substance is typically formulated with other,non-biologically active compounds to provide a means of predictable andquantitative dosage delivery, or perhaps to impart acceptable stabilityfeatures to the drug product. What is meant by a drug product is aformulation, mixture or admixture of the drug substance withcombinations of excipients, processing aids, buffers and perhaps otherinert ingredients that allow delivery of the drug substance by theselected delivery mechanism to the patient at a predictable dosage (thecarrier matrix). Various delivery mechanisms include solid oral dosage,for example, pills, tablets, or capsules. Additional delivery systemscan include solution or suspension injection dosage forms (includingdepo drug products), transdermal patches, and nasal or inhalationdevices. The dosage is the actual concentration delivered to thepatient, and depending upon many factors and the actual delivery systemselected, the dosage may be available for essentially immediate release,release over time, or manipulated by additional means for stimulatedrelease such as for example, by irradiation. Immediate release isdefined as a drug substance wherein under simulated gastric conditionsat least 85% is released within 1 hour.

It is a well-known chemical principle that an acid and a base will reactto form a salt. It is sometimes possible to predict the physical andchemical properties of these compounds in generalized concepts such aswhich way a melting point will change compared to the un-reacted acid orbase. Dissolution and dissociation rates of drug salts and theirassociated achievable solution concentrations are substantially lesspredictable when attempting to correlate this experimental data to someanticipated bio-availability of the drug. For instance, at a given pH,an observed dissolution rate and the associated solution concentrationof the drug may be dissociation controlled (i.e. ionization) rather thangoverned strictly by solubility parameters. Indeed, different salts ofthe same amine-containing active ingredient are likely to displaydiverging mechanisms of bio-availability as a function of pH. As such,an evaluation of amine-containing active ingredients and their differentsalts would help elucidate their bio-availability mechanisms. Thisapproach could be incorporated into a broader design feature to addressdrug abuse.

API salts and their polymorphs often exhibit different dissolutioncharacteristics. For instance the rate of dissolution is pH dependent,and therefore yields a different pharmacokinetic profile and/ortherapeutic efficacy. Sometimes, a given drug product formulationexpertise or technology can dominate any biological effects the API saltand/or polymorph present. Conversely, drug product formulation and theresulting mechanical properties of a tablet, capsule or bead can bedominated by the physical behavior of the API salt and/or its particularcrystal structure. It is not unusual that difficult trade-offs must bemade between the ease of manufacture of the drug product and thepharmacokinetics desired.

Drug product formulation can impact the pharmacokinetics of an API saltcandidate (and potential polymorph) by a host of technologies, includingbut not limited to, preparing formulated beads, different sized beads,coated beads, combinations of various bead technologies, formulatedmatrix systems, addition of hydrophobic layers to tablets, capsules orbeads (for example, as a control mechanism to limit the dissolution rateof hydrophilic gelatin capsules), coated tablets and capsules, capsulesfilled with beads, and different mixtures of beads with differentcoatings. These formulation techniques make available a wide range ofdrug product properties including, but not limited to, slow release,controlled release, and extended release drug pharmacokinetics. Theseactivities are dependent upon the API salt selected (and potentialpolymorph issues) because of the salt's dissolution profile at the pHwhere drug release is to occur (for liberation of the API from its saltform). In fact, different API salts and formulation techniques can beselected based on where the desired release is to occur in thegastrointestinal tract and the formulator can use the API salt's pKa,solubility, melting point, shape and particle size as primary factors toutilize, moderate or overcome localized insolubility through the use offormulation techniques.

The term “drug system” refers to a dosage wherein at least two doses areprovided. The two doses can be concurrent, sequential, or overlappingand each dose, of the two doses, may be the same or different.

Throughout the specification the term organic acid is used genericallyto refer to the acid form or the salt form of a compound.

EXPERIMENTAL METHODS

Differential Scanning Calorimetry (DSC)

Samples were evaluated using a Differential Scanning calorimeter from TAInstruments (DSC 2010). Prior to analysis of samples, a single-pointcalibration of the TA Instruments DSC 2010 Differential Scanningcalorimeter (DSC 2010) with the element indium as calibration standard(156.6±0.25° C.) was completed.

Infrared Spectroscopy (FTIR)

IR Spectra were obtained in a KBr disc using a Perkin Elmer Spectrum BXFourier Transform Infrared Spectrophotometer.

Powder X-Ray Diffraction (PXRD)

Powder X-Ray diffraction patterns were acquired on a Scintag XDS2000powder diffractometer using a copper source and a germanium detector. Apowder is defined herein as amorphous if the counts per second of theunderlying broad (>20 Deg. 2Theta at half height) absorption exceeds thecounts per second of narrow (<5 Deg. 2Theta at half height) peaks risingthere above. A powder is defined herein as crystalline if the counts persecond of the underlying broad (>20 Deg. 2Theta at half height)absorption is less than the counts per second of narrow (<5 Deg. 2Thetaat half height) peaks rising there above. Crystalline andpolycrystalline are not distinguished herein. Crystalline materials aredefined as having a morphology even if the actual morphology is notelucidated. Polycrystalline materials are defined as being polymorphic.

HPLC

HPLC analyses were performed on a Waters 2695 HPLC system equipped witha Waters 2996 photo diode array detector.

¹H NMR Spectroscopy

¹H NMR spectra were obtained on a 300 MHz Varian Gemini 2000spectrometer. Spectra were referenced to solvent (DMSO-d₆).

Example 1 Preparation of Oxycodone Free Base

To a 150 mL beaker was charged 10.0 g oxycodone hydrochloride and 100 mLwater. Concentrated ammonium hydroxide (2.6 grams) was then added tobring the pH to approximately 9. The product was collected by vacuumfiltration, washed with cold water and dried for about 5 hours undervacuum to provide 8.3 g (93% yield) of a white solid consistent instructure with oxycodone free base. This procedure was used to preparehydrocodone, hydromorphone and morphine free base as needed.

Example 2 Oxycodone Pamoate (Amorphous)

To a 100 mL one neck round bottom flask equipped with a magnetic stirbar, thermo-well and nitrogen inlet was charged oxycodone free base (3.0g) as prepared in Example 1. DMF (50 mL, 99.9% HPLC grade) was thenadded which produced a clear colorless solution. Pamoic acid (1.85 g,99%) was subsequently added over thirty seconds which produced a clearyellow solution. The solution was stirred under nitrogen for about 1.5hours at ambient temperature and then subsequently filtered through amedium fritted glass filter to remove any particulates. The filtrate wastransferred to a 1 L one-neck round bottom flask and about 750 mLiso-propanol was added over about one minute upon which a flocculentwhite precipitate formed. The mixture was stored in the refrigeratorovernight and the off-white solids collected by vacuum filtration(Whatman #4 filter paper). The product was washed with about 200 mLiso-propanol and subsequently transferred to a 250 mL one-neck roundbottom flask. To the flask was then added about 90 mL iso-propanol andthe solvent removed from the slurry under reduced pressure at about 40°C. (rotary evaporator). This evaporation procedure was repeated twiceand the resulting product dried overnight under vacuum at ambienttemperature (to provide 3.8 g (79%) of an off-white solid which wasanalyzed by DSC (FIG. 1), HPLC (assay as 2:1 salt; amine:pamoate), FTIR(FIG. 2), KF (range 0.5-3% water; replicate synthetic preparations) andPXRD (FIG. 3). The PXRD diffractogram indicated the product wasamorphous.

The original mother liquor from above reaction was cooled in arefrigerator overnight and the resulting product collected byfiltration, washed with a small portion of iso-propanol and driedovernight under vacuum (ambient temperature) to provide an additional0.4 g product (8% yield second crop, 87% total yield) with analyticalresults consistent with those reported above.

Example 3 Preparation of Oxycodone Pamoate (1^(st) Polymorphic Form)

To a 50 mL one neck round bottom flask equipped with a magnetic stirbar, thermowell and nitrogen inlet was charged oxycodone free base (1.3g, 99%) as prepared in Example 1. DMF (22 mL, HPLC grade) was then addedwhich produced a clear colorless solution. Pamoic acid (0.80 g, 99%) wassubsequently added over about thirty seconds which produced a clearyellow solution. The solution was stirred under nitrogen for about 1.5hours at ambient temperature and then subsequently vacuum filteredthrough a medium fritted glass filter to remove any particulates. Thefiltrate was transferred to a 250 mL one-neck round bottom flask and 45g iso-propanol was added to make the solution slightly turbid. Themixture was allowed to stir at ambient temperature overnight upon whichoff-white solids formed. The product was collected by filtration(Whatman #4 filter paper) and washed with a small portion ofiso-propanol. The product was dried overnight at ambient temperature andunder reduced pressure to provide 1.8 g (86%) of an off-white solidwhich was analyzed by DSC (FIG. 4), HPLC (assay 2:1 salt,amine:pamoate), FTIR (FIG. 5), KF (range 2-5% water; replicate syntheticpreparations) and PXRD (FIG. 6). The PXRD diffractogram confirmed theproduct was a polymorphic form of oxycodone pamoate.

The original mother liquor from above reaction later deposited morecrystals which were collected by filtration, washed with a small portionof iso-propanol and dried overnight under reduced pressure (ambienttemperature) to provide an additional 0.2 g (9.5% yield second crop,95.5% total yield) of material analytically consistent with the firstcrystals isolated.

Example 4 Preparation of Oxycodone Pamoate in 2^(nd) Polymorphic Form

To a 50 mL round bottom flask equipped with a magnetic stir bar, refluxcondenser and nitrogen inlet was charged oxycodone pamoate (amorphous,1.0 g, as prepared in Example 2) and acetone (14.9 g). The mixture washeated and maintained at reflux overnight under nitrogen upon which allthe material dissolved. The flask was then allowed to cool to ambienttemperature upon which a white solid formed. The solid was collected byfiltration, washed with a small portion of acetone (˜5 mL) and driedovernight under reduced pressure and at ambient temperature to provide0.8 g of a white solid (80% recovery). The product was characterized by,DSC (FIG. 98), FTIR (FIG. 99), KF (range 2-5% water; replicate syntheticpreparations), PXRD (FIG. 100) and ¹H-NMR (FIG. 101). Accordingly, theFTIR and ¹H-NMR spectra were absent evidence of acetone inclusion in thecrystal; the PXRD diffractogram confirmed the material's polymorphicnature yet different from that described in Example 3.

Example 5 Preparation of Oxycodone Xinafoate

To a 50 mL one neck round bottom flask equipped with a magnetic stirbar, thermowell and nitrogen inlet was charged oxycodone free base (0.5g) as prepared in Example 1. DMF (8 mL, HPLC grade) was then added whichproduced a clear colorless solution. BON acid (3-hydroxy-2-naphthoicacid, 0.298 g) was subsequently added over about thirty seconds whichproduced a clear yellow solution. The solution was stirred undernitrogen for about 2 hours at ambient temperature. To the clear solutionwas added MTBE (methyl t-butylether, 2 mL) and the solution placed in afreezer overnight. The product was subsequently collected by filtration(Whatman #4 filter paper) and washed with a small portion of MTBE anddried overnight under reduced pressure and at ambient temperature toprovide 0.5 g (63%) of a light-orange solid which was analyzed by DSC(FIG. 7), HPLC, FTIR (FIG. 8), KF (range 0.5-3% water; replicatesynthetic preparations) and PXRD (FIG. 9). PXRD confirmed the productwas partially crystalline.

Example 6 Preparation of Amorphous Hydrocodone Pamoate

A solution of hydrocodone free base (4.8 g), prepared in an analogousmanner as the procedure described in Example 1, in about 60 mL of DMF(HPLC grade) was treated with 3.1 g of pamoic acid with stirring atabout 25° C. The resulting mixture became a clear yellow solution afterabout 5 minutes and was stirred for about an additional 45 minutes. TheDMF solution was diluted with 600 mL of isopropyl alcohol and chilled toabout 7° C. for overnight. A yellow-tan precipitate was formed which wasisolated on a Buchner funnel and washed with fresh isopropyl alcohol.The material was re-slurried in isopropyl alcohol and the slurry wasstripped to dryness under reduced pressure on a rotary evaporator. There-slurry/stripping process was repeated twice whereupon the materialwas isolated yielding yield 6.6 g (84%) of a dry powder. The product wasanalyzed by DSC (FIG. 10), FTIR FIG. 11), HPLC (assay 2:1 salt;amine:pamoate), KF (range 1-5%; replicate synthetic preparations) andPXRD (FIG. 12). The PXRD diffractogram indicated the material wasamorphous.

Example 7 Preparation of Amorphous Hydrocodone Pamoate Acetone Solvate)

To a 50 mL round bottom flask equipped with a magnetic stir bar, refluxcondenser and nitrogen inlet was charged hydrocodone pamoate (amorphous,0.8 g, see Example 6) and acetone (˜20 mL). The mixture was heated andmaintained at reflux overnight under nitrogen upon which all thematerial dissolved. The flask was allowed to cool to ambient temperatureand concentrated under reduced pressure (rotary evaporator) to providean off-white solid. The product was dried overnight under vacuum atambient temperature to provide 0.6 g (75% recovery) of a white solid.The material was characterized by DSC, FTIR, PXRD and ¹H-NMR. The FTIRand ¹H-NMR spectra confirmed the inclusion of acetone; the PXRDdiffractogram indicated the product was amorphous.

Example 8 Preparation of Hydrocodone Pamoate (Polymorphic)

A solution of 6.5 g disodium pamoate in about 100 mL of USP water wastreated with enough 1N sodium hydroxide solution to adjust the pH toabout 9.0-9.5. The resulting solution was treated with a second solutionof hydrocodone hydrochloride prepared by slurrying 9.0 g of hydrocodonebase in about 100 mL of USP water and adding enough 1N hydrochloric acidto adjust the pH to 4.0-4.5. The hydrocodone solution was added in adropwise manner to the disodium pamoate solution over a period of about25 minutes at about 25° C. The resulting mixture was warmed to about 50°C. and samples were removed periodically for analysis by DSC. Afterapproximately 120 hours the product was filtered and washed with waterand dried. The resulting sample weighed 14.4 g and contained about 4moles of water as analyzed by coulometric titration. The material wasfurther characterized by DSC, HPLC, FTIR, and PXRD. The PXRDdiffractogram indicated the material was amorphous and similar incharacter to that obtained in Example 6. A portion (1.0 g) was dissolvedin DMF (8.0 g) to produce a yellow solution which was stirred undernitrogen at room temperature. Iso-propanol (˜16.1 g) was then added andthe solution stirred at ambient temperature for about 1 hour. The solidswere then collected by filtration, washed with iso-propanol and driedunder vacuum to provide 0.1 g. A second crop of crystals later formed inthe mother liquor which were collected by filtration and washed withiso-propanol to provide an additional 0.6 g. The collected solids fromthe two crops were found to be identical as characterized by DSC (FIG.13), HPLC (assay as 2:1 salt; amine:pamoate), FTIR (FIG. 14), KF (range1-4% water; replicate synthetic preparations) and PXRD (FIG. 15). ThePXRD diffractogram indicated the material was crystalline.

Example 9 Preparation of Hydrocodone Xinafoate

To a 100 mL one neck round bottom flask equipped with a magnetic stirbar, thermowell and nitrogen inlet was charged hydrocodone free base(1.0 g). DMF (˜14 mL, HPLC grade) was then added and produced a clearcolorless solution. To the solution was added BON acid(3-hydroxy-2-naphthoic acid, 0.629 g) over about thirty seconds whichproduced a clear yellow solution. The solution was stirred undernitrogen at ambient temperature for about 1 hour. To the clear solutionwas added about 184 g iso-propanol and the solution placed in arefrigerator (˜5° C.) overnight. A precipitate was collected byfiltration (Whatman #4 filter paper), washed with a small portion ofiso-propanol and dried overnight under reduced pressure at ambienttemperature to provide 1.3 g (80%) of an off-white solid characterizedby DSC (FIG. 16), HPLC, FTIR (FIG. 17), KF (range 0-4% water; replicatesynthetic preparations) and PXRD (FIG. 18). The PXRD diffractogramconfirmed the material was crystalline.

Example 10 Preparation of Amorphous Hydromorphone Pamoate

A solution of 4.3 g of disodium pamoate in about 50 mL USP water wastreated with enough 0.01N sodium hydroxide solution to adjust the pH toabout 9.0-9.5. The resulting solution was treated with a second solutionof hydromorphone hydrochloride prepared by dissolving 3.2 g ofhydromorphone hydrochloride in about 50 mL USP water and adding enough0.1N hydrochloric acid to adjust the pH to about 4.0-4.5. Thehydromorphone solution was added in a dropwise manner to the disodiumpamoate solution over a period of about 5 minutes at about 20° C. Theresulting mixture was stirred at ambient temperature for about 2 hoursduring which time a precipitate formed. The product was filtered andwashed with water and dried in vacuo. The material was characterized byHPLC, DSC (FIG. 19), FTIR (FIG. 20), KF (range 1-5% water, replicatesynthetic preparations); HPLC (2:1 salt; amine:pamoate) and PXRD (FIG.21). The PXRD diffractogram indicated the material was amorphous. Thereagent molar equivalents had been combined in a ratio to prepare the1:1 amine:pamoate salt yet the 2:1 salt was isolated. Similarly, the 2:1salt was also isolated from material prepared analogous to the proceduredescribed in Example 3 with the exception however, the reagent molarequivalents were charged in a 1:1 ratio.

Example 11 Preparation of Hydromorphone Pamoate (Polymorphic AcetoneSolvate)

To a 100 mL round bottom flask equipped with a magnetic stir bar, refluxcondenser and nitrogen inlet was charged hydromorphone pamoate(amorphous, 500 mg) and acetone (˜50 mL). The mixture was heated andmaintained at reflux overnight under nitrogen. The white slurry formedwas allowed to cool to ambient temperature, solids collected byfiltration and dried overnight under vacuum and at ambient temperatureto provide 0.5 g of an off-white solid. The product was characterized byDSC (FIG. 22), FTIR (FIG. 23), PXRD (FIG. 24), KF (˜2% water) and¹H-NMR. The FTIR and ¹H-NMR spectra indicated the material isolatedcontained acetone (about one equivalent); proton integration confirmedthe salt form was the 2:1 ratio of amine:pamoate. The PXRD indicated thematerial was crystalline.

Example 12 Preparation of Hydromorphone Xinafoate

A slurry of 1.9 g of 3-hydroxy-2-naphthoic acid (BON acid) in about 50mL USP water was treated with enough 1N sodium hydroxide solution toadjust the pH to about 9.0-9.5. The resulting solution was treated witha second solution of 3.2 grams of hydromorphone hydrochloride in 50 mLUSP water. The pH of the hydromorphone solution was adjusted to about4.0-4.5 by addition of a small amount of dilute hydrochloric acid. Thehydromorphone solution was added in a dropwise manner to the naphthoatesolution over a period of several minutes at about 20° C. The resultingmixture was stirred at ambient temperature for about 1 hour and thenheated briefly to 50° C. The reaction mixture was allowed to cool toambient temperature and was left stirring under nitrogen for about 18hours. The aqueous reaction liquor was decanted from the gummy productand the product was re-dissolved in about 200 mL acetone. After briefwarming, the product crystallized, the precipitate collected byfiltration, and air dried to give 3.1 g of crystalline material. Thematerial was characterized by DSC (FIG. 25), FTIR (FIG. 26), HPLC andPXRD (FIG. 27).

Example 13 Preparation of Morphine Pamoate (Amorphous)

A solution of 3.03 g of morphine in about 30 mL DMF was treated with3.88 g pamoic acid and the mixture stirred at about 25° C. The mixturebecame a clear yellow solution after about 5 minutes and was stirred foran additional 30 minutes. The DMF solution was diluted with isopropylalcohol (IPA) until turbidity was observed and reaction mixture chilledovernight at about 7° C. A yellow-tan precipitate was collected on aBuchner funnel and washed with fresh isopropyl alcohol. The gummymaterial was re-slurried in isopropyl alcohol and the solvent removedunder reduced pressure (rotary evaporator). The re-slurry/strippingprocess was repeated twice and the dry material was scraped from theflask to give 2.5 g of powder. The DMF/IPA filtrates werere-concentrated and re-diluted with 50 mL isopropyl alcohol to yield asecond crop of material which was subjected three times to the isopropylalcohol slurry/drying process as described for the first crop Theisolation and crystallization process for the second crop yieldedanother 1.5 g of material which was characterized by ¹H NMR (2:1 salt;amine:pamoate), DSC (FIG. 28), FTIR (FIG. 29), and PXRD (FIG. 30.

Example 14 Preparation of Morphine Pamoate (Polymorphic Acetone Solvate)

To a 100 mL round bottom flask equipped with a magnetic stir bar, refluxcondenser and nitrogen inlet was charged morphine pamoate (amorphous,400 mg; see Example 13) and acetone (˜50 mL). The mixture was heated andmaintained at refluxed overnight and under nitrogen whereupon almost allof the material dissolved. The flask was allowed to cool to ambienttemperature and white solid formed. The solid was collected byfiltration and dried overnight under vacuum to provide 0.3 g of anoff-white solid. The product was characterized by DSC (FIG. 31, FTIR(FIG. 32), PXRD (FIG. 33) and ¹H-NMR. The FTIR and ¹H-NMR confirmed theproduct contained about one equivalent of acetone. The PXRDdiffractogram indicated the product was crystalline.

Example 15 Preparation of Morphine Xinafoate

A slurry of 1.88 g of 3-hydroxy-2-naphthoic acid (BON acid) in about 25mL USP water was treated with enough 1N sodium hydroxide solution toadjust the pH to about 9.0-9.5. The resulting solution was treated witha second solution of morphine hydrochloride prepared by slurrying 3.0 gof morphine base in 25 mL USP water and adding enough 1N hydrochloricacid to adjust the pH to about 4.0-4.5. The morphine solution was addedin a dropwise manner to the naphthoate solution over a period of about 5minutes at about 20° C. The resulting mixture was stirred at ambienttemperature for about 1 hour and then heated briefly to 50° C. Thereaction mixture was allowed to cool to ambient temperature and was leftstirring under nitrogen for about 72 hours. The product was filtered,washed with water, and dried under vacuum. The resulting sample weighed4.4 g and contained about 1 equivalent of water by coulometrictitration. The material was further characterized by, DSC (FIG. 34),FTIR (FIG. 35) and PXRD (FIG. 36). The PXRD diffractogram indicated thematerial was crystalline.

Example 16 Dissolution Procedure

The opioid salts of the present invention were tested to determine theirdissolution profile as a function of pH, and as a function of ethanolconcentration in acidic media (dose dumping). To perform theseexperiments the buffered dissolution media and acidic ethanol solutionswere prepared as identified herein, “Preparation of Solutions”. The testprocedure was derived from the procedures cited in the United StatesPharmacopeia and National Formulary (USP), numbers <1087> and <711>. Thedose dumping procedure was adopted from the United States Food and DrugAdministration's guidance regarding the dose dumping of oxymorphone. Thesampling interval and regimen was defined and each sample analyzed byHPLC. Results from the HPLC analyses were plotted as a function of timeand dissolution condition (FIG. 37 through FIG. 97 inclusive, and FIGS.102-105). This procedure was used to obtain the pH and dose dumpingdissolution profiles disclosed herein. Verb tense within the proceduredescription does not indicate a prospective condition but was used tofacilitate the method's description herein. All activities within theprocedure were conducted and executed for each of the compounds reportedherein. Unless otherwise stated HPLC measurements were done and reportedat ambient temperature and dissolution testing was done nominally at 37°C.

Mean plasma concentration studies would be done in accordance withstandard procedures as set forth in U.S. Pat. No. 5,549,912 which isincorporated herein by reference. Suitable test and control formulationswould be prepared in accordance with the teachings herein. Apredetermined number of appropriate subjects would be treated with testformulations and an appropriate number of subjects would be treated withcontrol formulations. Control formulations may include placebos oractual pharmaceutical formulations. Pain could be monitored over aperiod of time and the relative pain between the groups compared.Alternatively, plasma concentrations could be determined, such as byhigh performance liquid chromatography, with subsequent determination ofmeans and half-lives for comparison. One would expect the inventivesamples to demonstrate no increase in blood plasma level due to ingestedalcohol versus comparative samples.

Preparation of Solutions:

All reagents are ACS grade or equivalent. All solvents used are aminimum of HPLC grade. Water used in the preparations of all solutionswas USP grade. These solution preparations are identical to thosedescribed in USP.

Preparation of 0.1N HCl:

To prepare 4 L of solution, add 33.3 mL of concentrated HCl to 977.7 mLof water, then add an additional 3000 mL of water.

Preparation of pH 4.5 Acetate Buffer:

To prepare 1 L of solution add 2.99 g of sodium acetate tri-hydrate(NaC₂H₃O₂.3H₂O) to a 1000 mL volumetric flask, then add 14.0 mL of 2Nacetic acid solution. Dissolve and dilute to volume with water.

Preparation of pH 6.8 Phosphate Buffer:

To prepare 200 mL of solution first prepare a 0.2 M potassium phosphatesolution by adding 27.22 g of monobasic potassium phosphate (KH₂PO₄) toa 1000 mL volumetric flask, then dissolve and dilute to volume withwater. Add 50 mL of this solution to a 200 mL volumetric flask, then add22.4 mL of 0.2M NaOH and dilute to volume with water.

Preparation of 5% Ethanol Solution for Dose Dumping DissolutionProfiles:

To prepare 900 mL of media combine 45 mL of 200 proof ethanol with 855mL of 0.1N HCl (see preparation procedure above).

Preparation of 20% Ethanol Solution for Dose Dumping DissolutionProfiles:

To prepare 900 mL of media combine 180 mL of 200 proof ethanol with 720mL of 0.1N HCl (see preparation procedure above).

Preparation of 40% Ethanol Solution for Dose Dumping DissolutionProfiles:

To prepare 900 mL of media combine 360 mL of 200 proof ethanol with 540mL of 0.1N HCl (see preparation procedure above).

Preparation of Mobile Phase A (0.1% TFA in H2O):

To prepare 1 L of mobile phase, add 1.0 mL of TFA to 1000 mL of H₂O. Mixwell and filter this solution through a 0.45 μM nylon filter.

Preparation of Mobile Phase B (0.1% TFA in Acetonitrile):

To prepare 1 L of mobile phase, add 1.0 mL of TFA to 1000 mL ofacetonitrile. Mix well and filter this solution through a 0.45 μM nylonfilter.

Preparation of Mobile Needle/Seal Wash solution:

To prepare 1 L of solution, add 500 mL of H₂O to 500 mL of acetonitrileand mix well.

Procedures:

Intrinsic Dissolution Profiles:

The following procedures were derived from USP <1087> IntrinsicDissolution and USP <711> Dissolution methods, as well as manufacturerrecommended procedures for use of the International CrystalsLaboratories intrinsic dissolution disks.

Preparation of API Pellet for Intrinsic Dissolution:

The material which is to be subjected to dissolution is weighed using ananalytical balance. 45.00-55 mg of the analyte was weighed andtransferred to an International Crystals Laboratories fixed/static disk316 stainless die with a 0.8 cm diameter die cavity. A hardened steelpunch was then inserted into the cavity and the material was compressedat 2000 psi for 4-5 minutes using a bench top hydraulic press. The punchis then removed to expose the 0.5 cm² pellet surface. A Viton gasket isthen placed around the threaded shoulder of the die and a polypropylenecap is threaded onto the die. This process can be repeated to generateas many pellets as is necessary for the experiment.

Setup of Intrinsic Dissolution Apparatus:

A Distek Dissolution System equipped with a model number TCSO200Ctemperature control system was filled with water and set to atemperature of 37.3° C. The vessel cavities were then equipped with four1 L flat-bottomed Distek dissolution vessels. Four vessels were thenfilled with 500 mL of the following media: 0.1N HCl, pH 4.5 acetatebuffer, pH 6.8 phosphate buffer, and USP grade water. The solutions wereallowed to warm in the water bath for approximately 1 hour, but notexceeding 3 hours, or until the temperature of the media matched that ofthe water bath. Paddles were then mounted to the Distek stirringapparatus above the four dissolution vessels such that the distancebetween the paddle and the die face is 1 inch. The paddle speed is thenset to 50 RPM.

Intrinsic Dissolution Dose Dumping Profiles:

The following procedures were derived from the FDA Draft Guidance forOxymorphone Hydrochloride (recommended in November, 2007).

Preparation of API Pellet for Intrinsic Dissolution Dose DumpingProfile:

The material which is to be subjected to dissolution is weighed using ananalytical balance. 85.00-95.00 mg of the analyte was weighed andtransferred to an International Crystals Laboratories fixed/static disk316 stainless die with a 0.8 cm diameter die cavity. A hardened steelpunch was then inserted into the cavity and the material was compressedat 2000 psi for 4-5 minutes using a bench top hydraulic press. The punchis then removed to expose the 0.5 cm² pellet surface. A Viton gasket isthen placed around the threaded shoulder of the die and a polypropylenecap is threaded onto the die. This process can be repeated to generateas many pellets as is necessary for the experiment.

Setup of Intrinsic Dissolution Apparatus for Dose Dumping Profile:

A Distek Dissolution System equipped with a model number TCS0200Ctemperature control system, was filled with water and set to atemperature of 37.3° C. The vessel cavities were then equipped with four1 L flat-bottomed Distek dissolution vessels. The vessels were thenfilled with 900 mL of the following media: 0.1N HCl, 5% ethanolsolution, 20% ethanol solution, and 40% ethanol solution. The solutionswere allowed to warm in the water bath for approximately 1 hour, but notexceeding 3 hours, or until the temperature of the media matched that ofthe water bath. Paddles were then mounted to the Distek stirringapparatus above the four dissolution vessels such that the distancebetween the paddle and the die face is 1 inch. The paddle speed is thenset to 75 RPM.

Performing an Intrinsic Dissolution Experiment (Dose Dumping or pHMedia):

The pellet prepared as described above was submerged into a vesselprepared as described above, with the pellet surface facing up (metaldie up, polypropylene cap facing down). Forceps are used to aid thisprocess so that the pellet apparatus can be gently placed into thebottom of the vessel. A timer is used to track the sampling intervals,and is started when the pellet is dropped into the solution. The lid tothe dissolution apparatus is then lowered and the stirring apparatus isactivated. Some planning is required in spacing out pellet drops suchthat each vessel can be sampled at the desired time intervals. Samplingis done by aspirating 10 mL of the solution using a Popper® Micro-Mate®Interchangeable Hypodermic Syringe equipped with a Vortex Pharma Group10 micron cannula porous filter. This filter should be replaced aftereach use. Although sampling intervals can change from experiment toexperiment, the following has been heavily utilized for the experimentsdescribed herein. Sampling occurring at t=0, 5, 10, 15, 30, 45, 60, 90,120, 150, 180 (minutes).

HPLC Methodology

HPLC Procedure for Analyzing Opioid Salts:

All samples should be analyzed with bracketing standard injections. Thestandard used should be from a qualified vendor with a known purity.Standard solutions should be prepared to have a concentration that isreasonably close to that of the samples being analyzed. All samples wererun on a Waters Alliance 2695 Separations Module model number WAT270008equipped with an Alliance 996 Photodiode Array Detector model number186000869. The instrument was equipped with an Agilent 300 Extend-C18 5μm 4.6×250 mm Zorbax column (PN 770995-902). The instrument was thenplumbed with the proper solutions mentioned above in the section titled“Preparation of Solutions”. The instrument is then set to initial columnconditions (see gradient table below):

Time (minutes) % A % B 0.00 90  10 2.00 90  10 8.00 25  75 8.01 0 10013.00 0 100 13.01 90  10 17.00 90  10

This method can be used to analyze samples to plot a dissolution profileor to determine the ratio of drug to organic salt. Due to thedifferences in response factors when dealing with an opioid salt(pamoate or xinafoate), a dilution is required to quantify the saltportion of the mixture.

The sample diluent that is utilized also has an impact on thechromatography when implementing this method. The following samplediluents were used when analyzing opioid salts for ratio analysis, aswell as dissolution profiles.

Opioid Diluent (H₂O:ACN) Oxycodone HCl 62:38 Hydrocodone Bitartrate62:38 Morphine Sulfate Pentahydrate 100:0 Hydromorphone HCl 100:0Oxycodone Pamoate or Xinafoate 62:38 Hydrocodone Pamoate or Xinafoate62:38 Morphine Pamoate or Xinafoate 90:10* Hydromorphone Pamoate orXinafoate 90:10* *More acetonitrile (ACN) may be added if a solutioncannot be obtained with this diluent

The invention has been described with particular focus on the preferredembodiments without limit thereto. One of skill in the art would realizeadditional embodiments and alterations which are not specifically statedbut which are within the mete and bounds as set forth in the claimsappended hereto.

The invention claimed is:
 1. A method of administering an activepharmaceutical comprising: providing a drug substance consisting of anorganic acid salt of an opioid as said active pharmaceutical whereinsaid drug substance does not have a wt % released at 30 minutes in 0.1 Nhydrochloric acid in USP water comprising 20% USP ethanol which ishigher than in 0.1 N hydrochloric acid in USP water without ethanolforming a drug product comprising said drug substance suitable forachieving a therapeutic dose of said drug substance in a predeterminedtime wherein when administered said therapeutic dose is not exceeded byingestion of alcohol at biological pH; wherein said drug substance isselected from the group consisting of: amorphous oxycodone pamoatecharacterized by a method selected from the group consisting of: adifferential scanning calorimetery thermogram of FIG. 1; an FTIR of FIG.2; and an X-ray diffraction diffractogram of FIG. 3; polymorphicoxycodone pamoate characterized by a method selected from the groupconsisting of: a differential scanning calorimetery thermogram of FIG.4; an FTIR of FIG. 5; and an X-ray diffraction diffractogram of FIG. 6;polymorphic oxycodone pamoate characterized by a method selected fromthe group consisting of: a differential scanning calorimetery thermogramof FIG. 98; an FTIR of FIG. 99; and an X-ray diffraction diffractogramof FIG. 100; hydrocodone xinafoate characterized by a method selectedfrom the group consisting of: a differential scanning calorimeterythermogram of FIG. 16; an FTIR of FIG. 17; and an X-ray diffractiondiffractogram of FIG. 18; and amorphous hydromorphone pamoatecharacterized by a method selected from the group consisting of: adifferential scanning calorimetery thermogram of FIG. 19; an FTIR ofFIG. 20; and an X-ray diffraction diffractogram of FIG.
 21. 2. Themethod of administering an active pharmaceutical of claim 1 wherein atleast 85 wt % of said opioid is bioavailable at 1 hour.
 3. The method ofadministering an active pharmaceutical of claim 1 wherein no more than85 wt % of said opioid is bioavailable at 1 hour.
 4. The method ofadministering an active pharmaceutical of claim 3 wherein at least 50 wt% to less than 85 wt % of said opioid is bioavailable at 1 hour.
 5. Themethod of administering an active pharmaceutical of claim 3 wherein saiddrug product is enteric coated and no more than 50 wt % of said opioidis bioavailable at 1 hour.
 6. The method of administering an activepharmaceutical of claim 5 wherein at least 12.5 wt % to no more than42.5 wt % of said opioid is bioavailable at 1 hour.
 7. The method ofadministering an active pharmaceutical of claim 1 wherein saidbiological pH is 1.6 to 7.2.
 8. The method of administering an activepharmaceutical of claim 1 wherein no more drug substance is released at1 hour in 0.1 N hydrochloric acid in USP water comprising 20% ethanolthan in 0.1 N hydrochloric acid in USP water without ethanol.
 9. Themethod of administering an active pharmaceutical of claim 1 wherein saiddrug product is provided in a form selected from the group consisting ofa tablet, a capsule, a caplet, and an oral suspension.
 10. The method ofadministering an active pharmaceutical of claim 1 wherein said drugproduct further comprises an additive.
 11. The method of administeringan active pharmaceutical of claim 10 wherein said additive comprises asecond opioid.
 12. The method of administering an active pharmaceuticalof claim 11 wherein said second opioid is selected from the groupconsisting of oxycodone, hydrocodone, morphine, apomorphine,hydromorphone, oxymorphone, codeine, dihydrocodeine, codeinone,thebaine, morphothebaine, thebenine, metathebainone,phenyldihydrothebaine, thebainhydroquinone, flavothebanone,alpha-codeimethine, acetylmethylmorphol, methylmorphenol,14-hydroxycodeinone, sinomenine, dihydrosinomenine, hasubanonine,levorphanol, nalbuphine, nalmefene, naloxone, naltrexone, noscapine,opium and oripavine.
 13. The method of administering an activepharmaceutical of claim 10 wherein said additive is defined by StructureH:

wherein R⁸-R¹¹ are independently selected from H, alkyl or substitutedalkyl of 1-6 carbons, adjacent groups may be taken together to form acyclic alkyl, cyclic alkyl-aryl, or cyclic aryl moiety; R¹² is selectedfrom H, or an alkali earth cation; R¹³ and R¹⁴ are independentlyselected from H, alkyl of 1-6 carbons, an alkali earth cation, and arylof 6 to 12 carbons, in a number sufficient to complete the valencebonding of X; and wherein X is selected from nitrogen, oxygen or sulfur.14. The method of administering an active pharmaceutical of claim 13wherein at least one of R¹² and R¹³ is an alkali earth cation.
 15. Themethod of administering an active pharmaceutical of claim 13 whereinsaid additive is selected from the group consisting of pamoic acid, analkali earth salt of pamoate, bon acid and an alkali earth salt of bonacid.
 16. The method of administering an active pharmaceutical of claim15 wherein said active pharmaceutical comprises disodium pamoate and atleast one drug substance selected from oxycodone pamoate, hydrocodonepamoate, morphine pamoate, hydromorphone pamoate, morphine,hydromorphone, oxycodone and hydrocodone.
 17. The method ofadministering an active pharmaceutical of claim 13 wherein said additiveand said pharmaceutically active compound are present in a molar ratioof between 0.5:1 and 1:1.
 18. The method of administering an activepharmaceutical of claim 10 wherein said additive is selected from thegroup consisting of binder, colorant, flow agent, disintegrants, releaseagent, surfactant, buffer, wetting agent and particle coating.